Oxazolidinones as taro inhibitors

ABSTRACT

Novel compounds of the structural formula I, and the pharmaceutically acceptable salts thereof, are inhibitors of TarO and may be useful in the prevention, treatment and suppression of diseases mediated by TarO, such as bacterial infections, including gram negative bacterial infections and gram positive bacterial infections such as MRSA and MRSE, alone or in combination with a β-lactam antibiotic.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a 371 of International Patent Application No.PCT/US2016/066284, filed Dec. 13, 2016, which claims priority from U.S.Provisional Patent Application Serial No. 62/268,141, filed Dec. 16,2015, the content of which is hereby incorporated by reference, in itsentirety.

BACKGROUND OF THE INVENTION

Bacterial antibiotic resistance has become one of the most seriousthreats to modem health care. Cohen, Science 1992, 257: 1051-1055discloses that infections caused by resistant bacteria frequently resultin longer hospital stays, higher mortality and increased cost oftreatment. Neu, Science 1992, 257: 1064-1073 discloses that the need fornew antibiotics will continue to escalate because bacteria have aremarkable ability to develop resistance to new agents rendering themquickly ineffective. There have been various efforts to elucidate themechanisms responsible for bacterial resistance, Coulton et al.,Progress in Medicinal Chemistry 1994, 31: 297-349 teaches that thewidespread use of penicillins and cephalosporins has resulted in theemergence of β-lactamases, a family of bacterial enzymes that catalyzethe hydrolysis of the β-lactam ring common to numerous presently usedantibiotics. More recently, Dudley, Pharmacotherapy 1995, 15: 9S-14S hasdisclosed that resistance mediated by β-lactamases is a critical aspectat the core of the development of bacterial antibiotic resistance.

Methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcusepidermidis (MRSE) have dramatically erroded the efficacy of β-lactamantibiotics. MRSA is emerging as a major cause of bloodstream infectionsin healthy individuals. In the 2013 Center for Disease Control andPrevention (CDC) Threat Level Report MRSA was designated as the secondleading cause of mortality by drug-resistant bacterial pathogen in theUS.

The most common mechanism of bacterial resistance to β-lactams involvesinactivation by β-lactamases, and a successful strategy to overcomeinactivation by combining a β-lactam and a β-lacatmase inhibitor hasbeen used clinically for Gram negative infections (Walsh, C. T. (2003)Antibiotics: Actions, Origins, Resistance, ASM Press, Washington, D.C.).However, Gram positive MRSA strains develop resistance through adifferent mechanism: the acquisition of a β-lactam resistantpeptidoglycan transpeptidase (TP) PBP2A (Beck, W. D., et al., J.Bacteriol. 165, 373-378 (1986); Hartman, B. J., and Tomasz, A. J.Bacteriol. 158, 513-516 (1984)).

The cell wall is the target of many widely used antibiotics, includingβ-lactams and glycopeptides. Wall teichoic acid (WTA) is an anionicglycophosphate polymer found as a major and integral component of mostGram-positive cell walls (Weidenmaier, C. and Peschel, A., Nature, April2008, Vol. 6, 278-287; Swoboda, J. G. et al, ACS Chem. Biol. 4, 875-83(2009); Lee, S. H. et al. Chemistry & Biology 18, 1379-89 (2011)).Although non-essential for S. aureus and B. subtilis at least underlaboratory conditions, WTA has been shown to play a critical role inenabling Gram positive bacteria to adhere to an infected host cells(Weidenmaier, C. and Peschel, A., Nature, April 2008, Vol. 6, 278-287);In addition, WTA plays key roles in cell growth, division, peptidoglycansynthesis and β-lactam resistance in methicillin resistantStaphylococcus aureus (MRSA) (Sewell, E. W. C., and Brown, E.d., J.Antibiotics (2014) 67, 43-51; Pasquina, L. W., et al., Current Opinionin Microbiology 2013, 16: 531-537).

S. aureus has been known to evade host innate and adaptive immunedefense system even though antibodies generated against S. aureusantigens are present in humans (Foster, Timothy J. Nature ReviewMicrobiology 2005, 3, 948-958). Recently, WTA, as part of the S. aureuscell wall, was implicated in preventing epitope recognition andosponization by antibodies in the host(Spiegel, David A. et al. ACSChemical Biology, Oct. 26, 2015 Just Accepted Manuscript). Therefore,WTA inhibitors can potentially sensitize pathogens to clearance by thehost adaptive immune system. This approach can also be potentiallyuseful for patients who have been previously administered S. aureusvaccine for the prevention of MRSA infections.

A recent study has shown that blocking the expression of wall teichoicacids (WTA) by inhibiting TarO, the first enzyme in the wall techoicacid biosyntheis in S. aureus, sensitizes methicillin-resistant S.aureus (MRSA) strains to β-lactams, even though β-lactam resistanttranspeptidase is expressed (Campbell, J. Et al., ACS Chemical Biology,Vol. 6, No. 1, pp. 106-116, 2011). The study further showed that WTAexpression is required for methicillin resistance to MRSA, and thatpreventing WTA biosynthesis by blocking TarO sensitizes MRSA strains toβ-lactams due to the combined inactivation of the native penicillinbinding proteins (PBP) and TarO. Further, the study showed thattreatment of a TarO mutant of MW2, a MRSA strain exhibiting moderateresistance to β-lactams, showed an 8-fold increase in sensitivity toβ-lactam antibiotics, including methicillin, imipenem, ceftazidime andcephradine, relative to the parent strain.

Finally, it has been suggested that Ticlopidine, an antiplatelet drug,may show low level activity against TarO and is only synergistic withthe β-lactam antibiotic, cefuroxime, and restores the efficacy ofcefuroxime in a community acquired MRSA strain USA300 (Sewell, E. W. C.,and Brown, E. D., J. Antibiotics (2014) 67, 43-51). Based on thesefindings, the combination of a TarO inhibitor with a β-lactam antibioticmay be useful for treating MRSA infections, particularly in β-lactamresistant MRSA and MRSE strains.

Due to the decrease in efficacy of β-lactam antibiotics, such asdicloxacillin, cefuroxime and cefepime in treating dangerous bacterialpathogens, there is a need for the development of antibiotic combinationagents to perserve the efficacy of β-lactams. The compounds of thepresent invention are novel TarO inhibitors which may be effective,alone or in combination with a β-lactam antibiotic, in preventing andtreating bacterial infections. The compounds of the present invention,alone or in combination with a β-lactam antibiotic, may also beeffective in enhancing bacterial clearance by the immune system.

Wall teichoic acids and their relevance to antibiotic resistance aredisclosed in: Sewell, Edward W. C., and Brown, E. D., Journal ofAntibiotics (2014), 67(1), 43-51; Pasquina, Lincoln W.; et al., CurrentOpinion in Microbiology (2013), 16(5), 531-537; Brown, E. D., et al.,ACS Chemical Biology (2013), 8(1), 226-233; Gilmore, M. S., et al.,Antimicrobial Agents and Chemotherapy (2011), 55(2), 767-774; andSwoboda, Jonathan G.; et al., ChemBioChem (2010), 11(1), 35-45.

WTA inhibitors are disclosed in Brown, E. D. et al., Bioorganic &Medicinal Chemistry Letters (2014), 24(3), 905-910; Liang, Lianzhu; etal., Chemistry & Biology (Oxford, United Kingdom) (2013), 20(2),272-284; Walker, S. et al., Bioorganic & Medicinal Chemistry Letters(2010), 20(5), 1767-1770; and WO2013148269.

SUMMARY OF THE INVENTION

The present invention relates to novel compounds of structural formulaI:

and pharmaceutically acceptable salts thereof. The compounds ofstructural formula I, and embodiments thereof, are inhibitors of TarOand may be useful in the prevention, treatment, and suppression ofdiseases, disorders and conditions mediated by inhibition of TarO, suchas bacterial infections. The compounds of the present invention, andpharmaceutically acceptable salts thereof, are also useful incombination with β-lactam antibiotics, such as imipenem anddicloxacillin, for the treatment of bacterial infections, particularlyantibiotic resistant bacterial infections such as methicillin-resistantStaphylocuccus aureus (MRSA) infections.

The present invention also relates to pharmaceutical compositionscomprising the compounds of the present invention, or pharmaceuticallyacceptable salts thereof, and a pharmaceutically acceptable carrier. Thepresent invention also relates to methods for the treatment, control orprevention of disorders, diseases, and conditions that may be responsiveto inhibition of TarO in a subject in need thereof by administering thecompounds of the present invention, or pharmaceutically acceptable saltsthereof, and pharmaceutical compositions of the present invention. Thepresent invention also relates to the use of compounds of the presentinvention, or pharmaceutically acceptable salts thereof, for manufactureof a medicament useful in treating diseases, disorders and conditionsthat may be responsive to the inhibition of TarO. The present inventionis also concerned with treatment of these diseases, disorders andconditions by administering the compounds of the present invention, orpharmaceutically acceptable salts thereof, in combination with atherapeutically effective amount of another agent that may be useful totreat the disease, disorder and condition. The invention is furtherconcerned with processes for preparing the compounds of the presentinvention, or pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is concerned with novel compounds of structuralFormula I:

or a pharmaceutically acceptable salt thereof; whereinA is selected from the group consisting of:

(1) aryl,

(2) heteroaryl,

(3) —O-aryl, and

(4) —O-heteroaryl,

wherein aryl and heteroaryl are unsubstituted or substituted with 1-5substituents selected from R^(a);

B is selected from the group consisting of:

(1) aryl, and

(2) heteroaryl,

wherein aryl and heteroaryl are unsubstituted or substituted with 1-4substituents selected from R^(b);

X is selected from the group consisting of:

(1) NR⁷,

(2) —CR⁸R⁹, and

(3) —O—;

Y is selected from the group consisting of:

(1) NR³,

(2) —CR¹⁰R¹¹, and

(3) —C(R¹²)═C(R¹³)—;

R¹ is selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —C₁₋₆alkyl, and

(4) —(CH₂)_(p)—OH,

wherein CH₂ and alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl;

R² is selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —C₁₋₆alkyl, and

(4) —(CH₂)_(p)—OH,

wherein CH₂ and alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl, or R¹and R² together with the carbon atom they are attached to form aC₃₋₆cycloalkyl ring, wherein the cycloalkyl ring is unsubstituted orsubstituted with 1-2 substituents selected from: halogen, —C₁₋₆alkyl,and —OC₁₋₆alkyl;R³ is selected from the group consisting of:

(1) hydrogen,

(2) OH, and

(3) —C₁₋₆alkyl,

wherein alkyl is unsubstituted or substituted with one to fivesubstituents selected from —C₁₋₆alkyl;

each R⁴ is independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —C₁₋₆alkyl, and

(4) —(CH₂)_(p)—OH,

wherein CH₂ and alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl;

each R⁵ is independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —C₁₋₆alkyl, and

(4) —(CH₂)_(p)—OH,

wherein CH₂ and alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl;

R⁶ is selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —C₁₋₆alkyl,

(4) —C₂₋₆alkenyl, and

(5) —(CH₂)—OH,

wherein CH₂, alkyl and alkenyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl;

R⁷ is selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —C₁₋₆alkyl,

(4) —C₂₋₆alkenyl, and

(5) —(CH₂)_(p)—OH,

wherein CH₂, alkyl and alkenyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl;

R⁸ is selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —C₁₋₆alkyl, and

(4) —(CH₂)—OH,

wherein CH₂ and alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl;

R⁹ is selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —C₁₋₆alkyl, and

(4) —(CH₂)—OH,

wherein CH₂ and alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl;

R¹⁰ is selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —C₁₋₆alkyl, and

(4) —(CH₂)—OH,

wherein CH₂ and alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl;

R¹¹ is selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —C₁₋₆alkyl, and

(4) —(CH₂)—OH,

wherein CH₂ and alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl;

R¹² is selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —C₁₋₆alkyl, and

(4) —(CH₂)—OH,

wherein CH₂ and alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl;

R¹³ is selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —C₁₋₆alkyl, and

(4) —(CH₂)—OH,

wherein CH₂ and alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl;

each R^(a) is independently selected from the group consisting of:

(1) halogen,

(2) —C₁₋₆alkyl,

(3) —OC₁₋₆alkyl,

(4) —OC₂₋₆alkenyl,

(5) —OH,

(6) oxo,

(7) —CN,

(8) —NO₂,

(9) —NR^(c)R^(d),

(10) —CH₂NR^(c)R^(d),

(11) —SO₂C₁₋₆alkyl,

(12) —C₃₋₆cycloalkyl,

(13) —C₂₋₆cycloheteroalkyl,

(14) aryl, and

(15) heteroaryl,

wherein —CH₂, alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl andheteroaryl are unsubstituted or substituted with 1-4 substituentsselected from: halogen, —C₁₋₆alkyl, —OC₁₋₆alkyl, and —CO₂C₁₋₆alkyl;

each R^(b) is independently selected from the group consisting of:

(1) halogen,

(2) —C₁₋₆alkyl,

(3) —C₂₋₆alkenyl,

(4) —OC₁₋₆alkyl,

(5) —OC₂₋₆alkenyl,

(6) —OH,

(7) oxo,

(8) —CN,

(9) —NO₂,

(10) —NR^(c)R^(d),

(11) —SO₂C₁₋₆alkyl,

(12) —C₃₋₆cycloalkyl,

(13) —C₂₋₆cycloheteroalkyl,

(14) aryl, and

(15) heteroaryl,

wherein alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl andheteroaryl are unsubstituted or substituted with 1-4 substituentsselected from: halogen, —C₁₋₆alkyl, —OC₁₋₆alkyl, and —CO₂C₁₋₆alkyl;

each R^(c) is independently selected from the group consisting of:

(1) hydrogen,

(2) C₁₋₆alkyl,

(3) C₂₋₆alkenyl,

(4) C₁₋₆alkyl-OH,

(5) C₃₋₆cycloalkyl,

(6) C(O)C₁₋₆alkyl, and

(7) SO₂C₁₋₆alkyl,

wherein alkyl, alkenyl and cycloalkyl are unsubstituted or substitutedwith one to three substituents selected from halogen, —C₁₋₆alkyl,—OC₁₋₆alkyl, and —CO₂C₁₋₆alkyl;

each R^(d) is independently selected from the group consisting of:

(1) hydrogen,

(2) C₁₋₆alkyl,

(3) C₂₋₆alkenyl,

(4) C₁₋₆alkyl-OH,

(5) C₃₋₆cycloalkyl,

(6) C(O)C₁₋₆alkyl, and

(7) SO₂C₁₋₆alkyl,

wherein alkyl, alkenyl and cycloalkyl are unsubstituted or substitutedwith one to three substituents selected from halogen, —C₁₋₆alkyl,—OC₁₋₆alkyl, and —CO₂C₁₋₆alkyl, or R^(c) and R^(d) together with thenitrogen atom they are attached to form a C₄₋₈cycloheteroalkyl ring,wherein the C₄₋₈cycloheteroalkyl ring is unsubstituted or substitutedwith 1-4 substituents selected from halogen, oxo, —C₁₋₆alkyl,—OC₁₋₆alkyl, and —CO₂C₁₋₆alkyl;m is 0 or 1;n is 0, 1, 2 or 3; andp is 0, 1, 2, 3, 4, 5 or 6.

The invention has numerous embodiments, which are summarized below. Theinvention includes the compounds as shown, and also includes individualdiastereoisomers, enantiomers, and epimers of the compounds, andmixtures of diastereoisomers and/or enantiomers thereof includingracemic mixtures.

In one embodiment of the present invention, A is selected from the groupconsisting of: aryl, heteroaryl, —O-aryl, and —O-heteroaryl, whereinaryl and heteroaryl are unsubstituted or substituted with 1-5substituents selected from R^(a).

In another embodiment of the present invention, A is selected from thegroup consisting of aryl, heteroaryl, and —O-aryl, wherein aryl andheteroaryl are unsubstituted or substituted with 1-5 substituentsselected from R^(a). In another embodiment of the present invention, Ais selected from the group consisting of: phenyl, naphthalene,tetrahydronaphthalene, isoquinoline, pyrazolo[1,5-a]pyridine,naphthyridine, quinoxaline, dihydrobenzodioxin, indole, indazole,thieno[3,2-c]pyridine, furo[2,3-c]pyridine, thiazole, quinoline,pyridine, pyrazole, quinazoline, dihydroisoindole,dihydrocyclopentan[b]pyridine, imidazo[2,1-b][1,3]thiazole,dihydropyrido[3,2-b][1,4]oxazine, benzothiophene, —O-phenyl,—O-naphthalene, isoindoline-1-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, andbenzo[d]oxazol-2(3H)-one, wherein A is unsubstituted or substituted with1-5 substituents selected from R^(a).

In another embodiment of the present invention, A is selected from thegroup consisting of phenyl, naphthalene, tetrahydronaphthalene,isoquinoline, pyrazolo[1,5-a]pyridine, naphthyridine, quinoxaline,dihydrobenzodioxin, indole, indazole, thieno[3,2-c]pyridine,furo[2,3-c]pyridine, thiazole, quinoline, pyridine, pyrazole,quinazoline, dihydroisoindole, dihydrocyclopentan[b]pyridine,imidazo[2,1-b][1,3]thiazole, dihydropyrido[3,2-b][1,4]oxazine,benzothiophene, —O-phenyl, and —O-naphthalene, wherein A isunsubstituted or substituted with 1-5 substituents selected from R^(a).

In another embodiment of the present invention, A is selected from thegroup consisting of aryl, and heteroaryl, wherein aryl and heteroarylare unsubstituted or substituted with 1-5 substituents selected fromR^(a). In another embodiment of the present invention, A is selectedfrom the group consisting of phenyl, naphthalene, tetrahydronaphthalene,isoquinoline, pyrazolopyridine, naphthyridine, quinoxaline,dihydrobenzodioxin, indole, indazole, thieno[3,2-c]pyridine,furopyridine, thiazole, quinoline, pyridine, pyrazole, quinazoline,dihydroisoindole, dihydrocyclopentan[b]pyridine, imidazothiazole,dihydropyrido oxazine, and benzothiophene, wherein A is unsubstituted orsubstituted with 1-5 substituents selected from R^(a). In anotherembodiment of the present invention, A is selected from the groupconsisting of: phenyl, naphthalene, tetrahydronaphthalene, isoquinoline,pyrazolo[1,5-a]pyridine, naphthyridine, quinoxaline, dihydrobenzodioxin,indole, indazole, thieno[3,2-c]pyridine, furo[2,3-c]pyridine, thiazole,quinoline, pyridine, pyrazole, quinazoline, dihydroisoindole,dihydrocyclopentan[b]-pyridine, imidazo[2,1-b][1,3]thiazole,dihydropyrido[3,2-b][1,4]oxazine, and benzothiophene, wherein A isunsubstituted or substituted with 1-5 substituents selected from R^(a).In another embodiment of the present invention, A is selected from thegroup consisting of: phenyl, naphthalene, isoquinoline,pyrazolo[1,5-a]pyridine, naphthyridine, quinazoline, and benzothiophene,wherein A is unsubstituted or substituted with 1-5 substituents selectedfrom R^(a).

In another embodiment of the present invention, A is selected from thegroup consisting of: phenyl, naphthalene, isoquinoline,pyrazolopyridine, naphthyridine, quinazoline, and benzothiophene,wherein A is unsubstituted or substituted with 1-5 substituents selectedfrom R^(a). In another embodiment of the present invention, A isselected from the group consisting of: phenyl, naphthalene,isoquinoline, pyrazolo[1,5-a]pyridine, 1,6-naphthyridine, quinazoline,and benzothiophene wherein A is unsubstituted or substituted with 1-5substituents selected from R^(a).

In another embodiment of the present invention, A is selected from thegroup consisting of: isoquinoline, and naphthyridine, wherein A isunsubstituted or substituted with 1-5 substituents selected from R^(a).In another embodiment of the present invention, A is selected from thegroup consisting of: isoquinoline and 1,6-naphthyridine, wherein A isunsubstituted or substituted with 1-5 substituents selected from R^(a).

In another embodiment of the present invention, A is aryl, wherein arylis unsubstituted or substituted with 1-5 substituents selected fromR^(a). In another embodiment of the present invention, A is selectedfrom the group consisting of: phenyl, naphthalene, and tetralin, whereinphenyl, naphthalene and tetralin are unsubstituted or substituted with1-5 substituents selected from R^(a). In another embodiment of thepresent invention, A is selected from the group consisting of: phenyl,and naphthalene, wherein phenyl and naphthalene are unsubstituted orsubstituted with 1-5 substituents selected from R^(a). In anotherembodiment of the present invention, A is phenyl, wherein phenyl isunsubstituted or substituted with 1-5 substituents selected from R^(a).In another embodiment of the present invention, A is naphthalene,wherein naphthalene is unsubstituted or substituted with 1-5substituents selected from R^(a). In another embodiment of the presentinvention, A is tetralin, wherein tetralin is unsubstituted orsubstituted with 1-5 substituents selected from R^(a).

In another embodiment of the present invention, A is heteroaryl, whereinheteroaryl is unsubstituted or substituted with 1-5 substituentsselected from R^(a).

In another embodiment of the present invention, A is selected from thegroup consisting of: isoquinoline, pyrazolo[1,5-a]pyridine,1,6-naphthyridine, quinoxaline, 2,3-dihydro-1,4-benzodioxine orbenzodioxane, indole, thieno[3,2-c]pyridine, furo[2.3-c]pyridine,thiazole, quinoline, pyridine, pyrazole, quinazoline,2,3-dihydroisoindole, 6,7-dihydro-5H-cyclopentan[b]pyridine,imidazo[2,1-b][1,3]thiazole, 2,3-dihydropyrido[3,2-b][1,4]oxazine,benzothiophene, isoindoline-1-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, andbenzo[d]oxazol-2(3H)-one, wherein A is unsubstituted or substituted with1-5 substituents selected from R^(a).

In another embodiment of the present invention, A is selected from thegroup consisting of: isoquinoline, pyrazolo[1,5-a]pyridine,1,6-naphthyridine, quinoxaline, 2,3-dihydro-1,4-benzodioxine orbenzodioxane, indole, thieno[3,2-c]pyridine, furo[2.3-c]pyridine,thiazole, quinoline, pyridine, pyrazole, quinazoline,2,3-dihydroisoindole, 6,7-dihydro-5H-cyclopentan[b]pyridine,imidazo[2,1-b][1,3]thiazole, 2,3-dihydropyrido[3,2-b][1,4]oxazine, andbenzothiophene, wherein A is unsubstituted or substituted with 1-5substituents selected from R^(a).

In another embodiment of the present invention, A is selected from thegroup consisting of: isoquinoline, pyrazolo[1,5-a]pyridine,1,6-naphthyridine, quinazoline, and benzothiophene, wherein A isunsubstituted or substituted with 1-5 substituents selected from R^(a).In another embodiment of the present invention, A is selected from thegroup consisting of: isoquinoline, and 1,6-naphthyridine, wherein A isunsubstituted or substituted with 1-5 substituents selected from R^(a).

In another embodiment of the present invention, A is isoquinoline,wherein A is unsubstituted or substituted with 1-5 substituents selectedfrom R^(a). In another embodiment of the present invention, A ispyrazolo[1,5-a]pyridine, wherein A is unsubstituted or substituted with1-5 substituents selected from R^(a). In another embodiment of thepresent invention, A is 1,6-naphthyridine, wherein A is unsubstituted orsubstituted with 1-5 substituents selected from R^(a). In anotherembodiment of the present invention, A is quinazoline, wherein A isunsubstituted or substituted with 1-5 substituents selected from R^(a).In another embodiment of the present invention, A is benzothiophene,wherein A is unsubstituted or substituted with 1-5 substituents selectedfrom R^(a).

In another embodiment of the present invention, B is selected from thegroup consisting of: aryl, and heteroaryl, wherein aryl and heteroarylare unsubstituted or substituted with 1-4 substituents selected fromR^(b).

In another embodiment of the present invention, B is selected from thegroup consisting of: phenyl, pyridine, and pyrimidine, wherein phenyl,pyridine and pyrimidine are unsubstituted or substituted with 1-4substituents selected from R^(b).

In another embodiment of the present invention, B is selected from thegroup consisting of: phenyl, and pyridine, wherein phenyl and pyridineare unsubstituted or substituted with 1-4 substituents selected fromR^(b). In another embodiment of the present invention, B is phenyl,wherein phenyl is unsubstituted or substituted with 1-4 substituentsselected from R^(b). In another embodiment of the present invention, Bis pyridine, wherein pyridine is unsubstituted or substituted with 1-4substituents selected from R^(b).

In another embodiment of the present invention, X is selected from thegroup consisting of: NR⁷, —CR⁸R⁹, and —O—. In another embodiment of thepresent invention, X is selected from the group consisting of: NR⁷, and—CR⁸R⁹. In another embodiment of the present invention, X is selectedfrom the group consisting of: NR⁷. In another embodiment of the presentinvention, X is selected from the group consisting of: —CR⁸R⁹.

In another embodiment of the present invention, Y is selected from thegroup consisting of: NR³, —CR¹⁰R¹¹, and —C(R¹²)═C(R¹³)—. In anotherembodiment of the present invention, Y is selected from the groupconsisting of: NR³ and —CR¹⁰R¹¹. In another embodiment of the presentinvention, Y is NR³. In another embodiment of the present invention, Yis —CR¹⁰R¹¹ In another embodiment of the present invention, Y is—C(R¹²)═C(R¹³)—.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of: hydrogen, halogen, —C₁₋₆alkyl, and —(CH₂)_(p)—OH,wherein CH₂ and alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of: hydrogen, —C₁₋₆alkyl, and —(CH₂)—OH, wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituentsselected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. In anotherembodiment of the present invention, R¹ is selected from the groupconsisting of: hydrogen, —C₁₋₆alkyl, and —(CH₂)—OH. In anotherembodiment of the present invention, R¹ is selected from the groupconsisting of: hydrogen, —CH₃, —CH₂CH₃, —CH₂OH, and —(CH₂)₂OH, whereinCH₂ and alkyl are unsubstituted or substituted with 1-2 substituentsselected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. In anotherembodiment of the present invention, R¹ is selected from the groupconsisting of: hydrogen, —CH₃, —CH₂CH₃, —CH₂OH, and —(CH₂)₂OH.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of: hydrogen, and —C₁₋₆alkyl, wherein alkyl isunsubstituted or substituted with 1-2 substituents selected from:halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of: hydrogen, —CH₃, and —CH₂CH₃. In another embodimentof the present invention, R¹ is selected from the group consisting of:hydrogen, and —CH₃.

In another embodiment of the present invention, R² is selected from thegroup consisting of: hydrogen, halogen, —C₁₋₆alkyl, and —(CH₂)_(p)—OH,wherein CH₂ and alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl, or R¹and R² together with the carbon atom they are attached to form aC₃₋₆cycloalkyl ring, wherein the cycloalkyl ring is unsubstituted orsubstituted with 1-2 substituents selected from: halogen, —C₁₋₆alkyl,and —OC₁₋₆alkyl.

In another embodiment of the present invention, R² is selected from thegroup consisting of: hydrogen, —C₁₋₆alkyl, and —(CH₂)—OH, wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituentsselected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl, or R¹ and R²together with the carbon atom they are attached to form a C₃₋₆cycloalkylring, wherein the cycloalkyl ring is unsubstituted or substituted with1-2 substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl.

In another embodiment of the present invention, R² is selected from thegroup consisting of: hydrogen, —C₁₋₆alkyl, and —(CH₂)—OH, wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituentsselected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl, or R¹ and R²together with the carbon atom they are attached to form a cyclopropylring, wherein the cyclopropyl ring is unsubstituted or substituted with1-2 substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. Inanother embodiment of the present invention, R² is selected from thegroup consisting of: hydrogen, —CH₃, —CH₂CH₃, —CH₂OH, and —(CH₂)₂OH, orR¹ and R² together with the carbon atom they are attached to form acyclopropyl ring, wherein the cyclopropyl ring is unsubstituted orsubstituted with 1-2 substituents selected from: halogen, —C₁₋₆alkyl,and —OC₁₋₆alkyl.

In another embodiment of the present invention, R² is selected from thegroup consisting of: hydrogen, —C₁₋₆alkyl, and —(CH₂)—OH, wherein CH₂and alkyl are unsubstituted or substituted with 1-2 substituentsselected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. In anotherembodiment of the present invention, R² is selected from the groupconsisting of: hydrogen, —CH₃, —CH₂CH₃, —CH₂OH, and —(CH₂)₂OH. Inanother embodiment of the present invention, R² is selected from thegroup consisting of: hydrogen, —CH₃, and —CH₂OH.

In another embodiment of the present invention, R¹ and R² are eachindependently selected from the group consisting of: hydrogen,—C₁₋₆alkyl, and —(CH₂)_(p)—OH, provided that one of R¹ and R² isselected from —C₁₋₆alkyl and —(CH₂)_(p)—OH. In another embodiment of thepresent invention, R¹ and R² are each independently selected from thegroup consisting of: hydrogen, —CH₃, —CH₂CH₃, —CH₂OH, and —(CH₂)₂OH,provided that one of R¹ and R² is selected from —CH₃, —CH₂CH₃, —CH₂OH,and —(CH₂)₂OH. In another embodiment of the present invention, R¹ and R²are each independently selected from the group consisting of: hydrogen,and —C₁₋₆alkyl, provided that one of R¹ and R² is selected from—C₁₋₆alkyl.

In another embodiment of the present invention, R¹ is hydrogen, and R²is —C₁₋₆alkyl. In another embodiment of the present invention, R¹ ishydrogen, and R² is —CH₃. In another embodiment of the presentinvention, R¹ is hydrogen and R² is hydrogen or —C₁₋₆alkyl. In anotherembodiment of the present invention, R¹ is hydrogen and R² is hydrogenor —CH₃.

In another embodiment of the present invention, R² is hydrogen, and R¹is —C₁₋₆alkyl. In another embodiment of the present invention, R² ishydrogen, and R¹ is —CH₃. In another embodiment of the presentinvention, R² is hydrogen and R¹ is hydrogen or —C₁₋₆alkyl. In anotherembodiment of the present invention, R² is hydrogen and R¹ is hydrogenor —CH₃.

In another embodiment of the present invention, R³ is selected from thegroup consisting of: hydrogen, OH, and —C₁₋₆alkyl, wherein alkyl isunsubstituted or substituted with one to five substituents selected from—C₁₋₆alkyl.

In another embodiment of the present invention, R³ is selected from thegroup consisting of: hydrogen, and —C₁₋₆alkyl, wherein alkyl isunsubstituted or substituted with one to five substituents selected from—C₁₋₆alkyl. In another embodiment of the present invention, R³ isselected from the group consisting of: hydrogen, OH, and —C₁₋₆alkyl.

In another embodiment of the present invention, R³ is selected from thegroup consisting of: hydrogen, and OH. In another embodiment of thepresent invention, R³ is —C₁₋₆alkyl. In another embodiment of thepresent invention, R³ is OH. In another embodiment of the presentinvention, R³ is hydrogen.

In another embodiment of the present invention, each R⁴ is independentlyselected from the group consisting of: hydrogen, halogen, —C₁₋₆alkyl,and —(CH₂)_(p)—OH, wherein CH₂ and alkyl are unsubstituted orsubstituted with 1-2 substituents selected from: halogen, —C₁₋₆alkyl,and —OC₁₋₆alkyl. In another embodiment of the present invention, each R⁴is independently selected from the group consisting of: hydrogen,—C₁₋₆alkyl, and —(CH₂)_(p)—OH, wherein CH₂ and alkyl are unsubstitutedor substituted with 1-2 substituents selected from: halogen, —C₁₋₆alkyl,and —OC₁₋₆alkyl. In another embodiment of the present invention, each R⁴is independently selected from the group consisting of: hydrogen,halogen, and —C₁₋₆alkyl, wherein alkyl are unsubstituted or substitutedwith 1-2 substituents selected from: halogen, —C₁₋₆alkyl, and—OC₁₋₆alkyl.

In another embodiment of the present invention, each R⁴ is independentlyselected from the group consisting of: hydrogen, halogen, and—C₁₋₆alkyl. In another embodiment of the present invention, each R⁴ isindependently selected from the group consisting of: hydrogen, and—C₁₋₆alkyl. In another embodiment of the present invention, each R⁴ is—C₁₋₆alkyl. In another embodiment of the present invention, each R⁴ ishydrogen.

In another embodiment of the present invention, each R⁵ is independentlyselected from the group consisting of: hydrogen, halogen, —C₁₋₆alkyl,and —(CH₂)_(p)—OH, wherein CH₂ and alkyl are unsubstituted orsubstituted with 1-2 substituents selected from: halogen, —C₁₋₆alkyl,and —OC₁₋₆alkyl. In another embodiment of the present invention, each R⁵is independently selected from the group consisting of: hydrogen,—C₁₋₆alkyl, and —(CH₂)_(p)—OH, wherein CH₂ and alkyl are unsubstitutedor substituted with 1-2 substituents selected from: halogen, —C₁₋₆alkyl,and —OC₁₋₆alkyl.

In another embodiment of the present invention, each R⁵ is independentlyselected from the group consisting of: hydrogen, halogen, and—C₁₋₆alkyl, wherein alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl.

In another embodiment of the present invention, each R⁵ is independentlyselected from the group consisting of: hydrogen, halogen, and—C₁₋₆alkyl. In another embodiment of the present invention, each R⁵ isindependently selected from the group consisting of: hydrogen, and—C₁₋₆alkyl. In another embodiment of the present invention, each R⁵ is—C₁₋₆alkyl. In another embodiment of the present invention, each R⁵ ishydrogen.

In another embodiment, R⁶ is selected from the group consisting of:hydrogen, halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, and —(CH₂)_(p)—OH, whereinCH₂ and alkyl and alkenyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. Inanother embodiment of the present invention, R⁶ is selected from thegroup consisting of: hydrogen, halogen, —C₁₋₆alkyl, and —C₂₋₆alkenyl,wherein alkyl and alkenyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. Inanother embodiment of the present invention, R⁶ is selected from thegroup consisting of: hydrogen, halogen, and —C₁₋₆alkyl, wherein alkylare unsubstituted or substituted with 1-2 substituents selected from:halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl.

In another embodiment of the present invention, R⁶ is selected from thegroup consisting of: hydrogen, halogen, and —C₁₋₆alkyl. In anotherembodiment of the present invention, R⁶ is selected from the groupconsisting of: hydrogen, and —C₁₋₆alkyl. In another embodiment of thepresent invention, R⁶ is —C₁₋₆alkyl. In another embodiment of thepresent invention, R⁶ is hydrogen.

In another embodiment of the present invention, R⁷ is selected from thegroup consisting of: hydrogen, halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, and—(CH₂)—OH, wherein CH₂, alkyl and alkenyl are unsubstituted orsubstituted with 1-2 substituents selected from: halogen, —C₁₋₆alkyl,and —OC₁₋₆alkyl.

In another embodiment of the present invention, R⁷ is selected from thegroup consisting of: hydrogen, —C₁₋₆alkyl, and —C₂₋₆alkenyl, whereinalkyl and alkenyl are unsubstituted or substituted with 1-2 substituentsselected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. In anotherembodiment of the present invention, R⁷ is selected from the groupconsisting of: hydrogen, and —C₂₋₆alkenyl, wherein alkenyl isunsubstituted or substituted with 1-2 substituents selected from:halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. In a class of this embodiment ofthe present invention, R⁷ is selected from the group consisting of:hydrogen and —CH₂CH═CH₂. In another embodiment of the present invention,R⁷ is selected from the group consisting of: —C₂₋₆alkenyl. In a class ofthis embodiment of the present invention, R⁷ is —CH₂CH═CH₂. In anotherembodiment of the present invention, R⁷ is hydrogen.

In another embodiment of the present invention, R⁸ is selected from thegroup consisting of: hydrogen, halogen, —C₁₋₆alkyl, and —(CH₂)_(p)—OH,wherein CH₂ and alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. Inanother embodiment of the present invention, R⁸ is selected from thegroup consisting of: hydrogen, and —C₁₋₆alkyl, wherein alkyl areunsubstituted or substituted with 1-2 substituents selected from:halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. In another embodiment of thepresent invention, R⁸ is selected from the group consisting of:—C₁₋₆alkyl, wherein alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. Inanother embodiment of the present invention, R⁸ is selected from thegroup consisting of: —C₁₋₆alkyl. In another embodiment of the presentinvention, each R⁸ is hydrogen.

In another embodiment of the present invention, R⁹ is selected from thegroup consisting of: hydrogen, halogen, —C₁₋₆alkyl, and —(CH₂)_(p)—OH,wherein CH₂ and alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. Inanother embodiment of the present invention, R⁹ is selected from thegroup consisting of: hydrogen, and —C₁₋₆alkyl, wherein alkyl areunsubstituted or substituted with 1-2 substituents selected from:halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. In another embodiment of thepresent invention, R⁹ is selected from the group consisting of:—C₁₋₆alkyl, wherein alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. Inanother embodiment of the present invention, R⁹ is selected from thegroup consisting of: —C₁₋₆alkyl. In another embodiment of the presentinvention, each R⁹ is hydrogen.

In another embodiment of the present invention, R¹⁰ is selected from thegroup consisting of: hydrogen, halogen, —C₁₋₆alkyl, and —(CH₂)_(p)—OH,wherein CH₂ and alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. Inanother embodiment of the present invention, R¹⁰ is selected from thegroup consisting of: hydrogen, and —C₁₋₆alkyl, wherein alkyl areunsubstituted or substituted with 1-2 substituents selected from:halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. In another embodiment of thepresent invention, R¹⁰ is selected from the group consisting of:—C₁₋₆alkyl, wherein alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. Inanother embodiment of the present invention, R¹⁰ is selected from thegroup consisting of: —C₁₋₆alkyl. In another embodiment of the presentinvention, each R¹⁰ is hydrogen.

In another embodiment of the present invention, R¹¹ is selected from thegroup consisting of: hydrogen, halogen, —C₁₋₆alkyl, and —(CH₂)_(p)—OH,wherein CH₂ and alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. Inanother embodiment of the present invention, R¹¹ is selected from thegroup consisting of: hydrogen, and —C₁₋₆alkyl, wherein alkyl areunsubstituted or substituted with 1-2 substituents selected from:halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. In another embodiment of thepresent invention, R¹¹ is selected from the group consisting of:—C₁₋₆alkyl, wherein alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. Inanother embodiment of the present invention, R¹¹ is selected from thegroup consisting of: —C₁₋₆alkyl. In another embodiment of the presentinvention, each R¹¹ is hydrogen.

In another embodiment of the present invention, R¹² is selected from thegroup consisting of: hydrogen, halogen, —C₁₋₆alkyl, and —(CH₂)_(p)—OH,wherein CH₂ and alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. Inanother embodiment of the present invention, R¹² is selected from thegroup consisting of: hydrogen, and —C₁₋₆alkyl, wherein alkyl areunsubstituted or substituted with 1-2 substituents selected from:halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. In another embodiment of thepresent invention, R¹² is selected from the group consisting of:—C₁₋₆alkyl, wherein alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. Inanother embodiment of the present invention, R¹² is selected from thegroup consisting of: —C₁₋₆alkyl. In another embodiment of the presentinvention, each R¹² is hydrogen.

In another embodiment of the present invention, R¹³ is selected from thegroup consisting of: hydrogen, halogen, —C₁₋₆alkyl, and —(CH₂)_(p)—OH,wherein CH₂ and alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. Inanother embodiment of the present invention, R¹³ is selected from thegroup consisting of: hydrogen, and —C₁₋₆alkyl, wherein alkyl areunsubstituted or substituted with 1-2 substituents selected from:halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. In another embodiment of thepresent invention, R¹³ is selected from the group consisting of:—C₁₋₆alkyl, wherein alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl. Inanother embodiment of the present invention, R¹³ is selected from thegroup consisting of: —C₁₋₆alkyl. In another embodiment of the presentinvention, each R¹³ is hydrogen.

In another embodiment of the present invention, each R^(a) isindependently selected from the group consisting of: halogen,—C₁₋₆alkyl, —OC₁₋₆alkyl, —OC₂₋₆alkenyl, —OH, oxo, —CN, —NO₂,—NR^(c)R^(d), —CH₂NR^(c)R^(d), —SO₂C₁₋₆alkyl, —C₃₋₆cycloalkyl,—C₂₋₆cycloheteroalkyl, aryl, and heteroaryl, wherein —CH₂, alkyl,alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl areunsubstituted or substituted with 1-4 substituents selected from:halogen, —C₁₋₆alkyl, —OC₁₋₆alkyl, and —CO₂C₁₋₆alkyl. In anotherembodiment of the present invention, each R^(a) is independentlyselected from the group consisting of: halogen, —C₁₋₆alkyl, —OC₁₋₆alkyl,—OC₂₋₆alkenyl, —OH, oxo, —CN, —NO₂, —NR^(c)R^(d), —CH₂NR^(c)R^(d),—SO₂C₁₋₆alkyl, —C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl, aryl, andheteroaryl, wherein CH₂, alkyl, alkenyl, cycloalkyl, cycloheteroalkyl,aryl and heteroaryl are unsubstituted or substituted with 1-4substituents selected from: halogen.

In another embodiment of the present invention, each R^(a) isindependently selected from the group consisting of: halogen,—C₁₋₆alkyl, —OC₁₋₆alkyl, oxo, —NO₂, —NR^(c)R^(d), —CH₂NR^(c)R^(d),—SO₂C₁₋₆alkyl, —C₂₋₆cycloheteroalkyl, and heteroaryl, wherein —CH₂,alkyl, cycloheteroalkyl and heteroaryl are unsubstituted or substitutedwith 1-4 substituents selected from: halogen, —C₁₋₆alkyl, —OC₁₋₆alkyl,and —CO₂C₁₋₆alkyl. In another embodiment of the present invention, eachR^(a) is independently selected from the group consisting of: halogen,—C₁₋₆alkyl, —OC₁₋₆alkyl, oxo, —NO₂, —NR^(c)R^(d), —CH₂NR^(c)R^(d),—SO₂C₁₋₆alkyl, —C₂₋₆cycloheteroalkyl, and heteroaryl, wherein —CH₂,alkyl, cycloheteroalkyl and heteroaryl are unsubstituted or substitutedwith 1-4 substituents selected from: halogen. In another embodiment ofthe present invention, each R^(a) is independently selected from thegroup consisting of: halogen, —C₁₋₆alkyl, —OC₁₋₆alkyl, oxo, —NO₂,—NR^(c)R^(d), —CH₂NR^(c)R^(d), —SO₂C₁₋₆alkyl, —C₂₋₆cycloheteroalkyl, andheteroaryl, wherein —CH₂, alkyl, cycloheteroalkyl, and heteroaryl areunsubstituted or substituted with 1-4 substituents selected from: F. Inanother embodiment of the present invention, each R^(a) is independentlyselected from the group consisting of: F, Br, Cl, —CH₃, —CF₃, —CH(CH₃)₂,—OCH₃, —OCH₂CH₃, —OCHF₂, oxo, —NO₂, —N(CH₃)₂, —CH₂N(CH₃)₂, —SO₂CH₃,morpholine, and pyrrole.

In another embodiment of the present invention, each R^(a) isindependently selected from the group consisting of: —C₁₋₆alkyl,—OC₁₋₆alkyl, oxo, and —NO₂, wherein alkyl is unsubstituted orsubstituted with 1-4 substituents selected from: halogen, —C₁₋₆alkyl,—OC₁₋₆alkyl, and —CO₂C₁₋₆alkyl. In another embodiment of the presentinvention, each R^(a) is independently selected from the groupconsisting of: —C₁₋₆alkyl, —OC₁₋₆alkyl, oxo, and —NO₂, wherein alkyl isunsubstituted or substituted with 1-4 substituents selected fromhalogen. In another embodiment of the present invention, each R^(a) isindependently selected from the group consisting of: —C₁₋₆alkyl,—OC₁₋₆alkyl, oxo, and —NO₂, wherein alkyl is unsubstituted orsubstituted with 1-4 substituents selected from F. In another embodimentof the present invention, each R^(a) is independently selected from thegroup consisting of: —CH₃, —CF₃, —CH(CH₃)₂, —OCH₃, —OCH₂CH₃, —OCHF₂,oxo, and —NO₂.

In another embodiment of the present invention, each R^(a) isindependently selected from the group consisting of: —CF₃, —OCH₃, oxo,and —NO₂.

In another embodiment of the present invention, each R^(b) isindependently selected from the group consisting of: halogen,—C₁₋₆alkyl, —C₂₋₆alkenyl, —OC₁₋₆alkyl, —OC₂₋₆alkenyl, —OH, oxo, —CN,—NO₂, —NR^(c)R^(d), —SO₂C₁₋₆alkyl, —C₃₋₆cycloalkyl,—C₂₋₆cycloheteroalkyl, aryl, and heteroaryl, wherein alkyl, alkenyl,cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted orsubstituted with 1-4 substituents selected from: halogen, —C₁₋₆alkyl,—OC₁₋₆alkyl, and —CO₂C₁₋₆alkyl. In another embodiment of the presentinvention, each R^(b) is independently selected from the groupconsisting of: halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —OC₁₋₆alkyl,—OC₂₋₆alkenyl, —OH, oxo, —CN, —NO₂, —NR^(c)R^(d), —SO₂C₁₋₆alkyl,—C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl, aryl, and heteroaryl, whereinalkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl areunsubstituted or substituted with 1-4 substituents selected from:halogen.

In another embodiment of the present invention, each R^(b) isindependently selected from the group consisting of: halogen,—C₁₋₆alkyl, —OC₁₋₆alkyl, —OC₂₋₆alkenyl, —NR^(c)R^(d), —C₃₋₆cycloalkyl,and —C₂₋₆cycloheteroalkyl, wherein alkyl, alkenyl, cycloalkyl, andcycloheteroalkyl are unsubstituted or substituted with 1-4 substituentsselected from: halogen, —C₁₋₆alkyl, —OC₁₋₆alkyl, and —CO₂C₁₋₆alkyl. Inanother embodiment of the present invention, each R^(b) is independentlyselected from the group consisting of: halogen, —C₁₋₆alkyl, —OC₁₋₆alkyl,—OC₂₋₆alkenyl, —NR^(c)R^(d), —C₃₋₆cycloalkyl, and —C₂₋₆cycloheteroalkyl,wherein alkyl, alkenyl, cycloalkyl, and cycloheteroalkyl areunsubstituted or substituted with 1-4 substituents selected from: F. Inanother embodiment of the present invention, each R^(b) is independentlyselected from the group consisting of: F, Br, Cl, —CH₃, —CF₃, —CHF₂,—C(CH₃)F₂, —OCH₃, —OCH₂CH₃, —OCF₃, —OCF₂CH₃, —OCH₂CH═CH₂, —N(CH₃)₂,cyclopropyl, and pyrrolidine.

In another embodiment of the present invention, each R^(b) isindependently selected from the group consisting of: halogen,—C₁₋₆alkyl, —OC₁₋₆alkyl, and —OC₂₋₆alkenyl, wherein alkyl, and alkenylare unsubstituted or substituted with 1-4 substituents selected from:halogen, —C₁₋₆alkyl, —OC₁₋₆alkyl, and —CO₂C₁₋₆alkyl. In anotherembodiment of the present invention, each R^(b) is independentlyselected from the group consisting of: halogen, —C₁₋₆alkyl, —OC₁₋₆alkyl,and —OC₂₋₆alkenyl, wherein alkyl, and alkenyl are unsubstituted orsubstituted with 1-4 substituents selected from: F. In anotherembodiment of the present invention, each R^(b) is independentlyselected from the group consisting of: F, Br, Cl, —CH₃, —CF₃, —CHF₂,—OCH₃, —OCH₂CH₃, —OCF₃, —OCF₂CH₃, and —OCH₂CH═CH₂. In another embodimentof the present invention, each R^(b) is independently selected from thegroup consisting of: F, Cl, —CF₃, —OCH₃, —OCH₂CH₃, —OCF₃, and—OCH₂CH═CH₂.

In another embodiment of the present invention, each R^(b) isindependently selected from the group consisting of: —C₁₋₆alkyl, and—OC₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with 1-4substituents selected from: halogen. In another embodiment of thepresent invention, each R^(b) is independently selected from the groupconsisting of: —C₁₋₆alkyl, and —OC₁₋₆alkyl, wherein alkyl isunsubstituted or substituted with 1-4 substituents selected from: F. Inanother embodiment of the present invention, each R^(b) is independentlyselected from the group consisting of: —CH₃, —CF₃, —CHF₂, —OCH₃,—OCH₂CH₃, —OCF₃, and —OCF₂CH₃. In another embodiment of the presentinvention, each R^(b) is independently selected from the groupconsisting of: —CF₃, —OCH₃, —OCH₂CH₃, and —OCF₃. In another embodimentof the present invention, each R^(b) is independently selected from thegroup consisting of: —CF₃, and —OCH₃.

In another embodiment of the present invention, each R^(c) isindependently selected from the group consisting of: hydrogen,—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₁₋₆alkyl-OH, —C₃₋₆cycloalkyl,—C(O)C₁₋₆alkyl, and SO₂C₁₋₆alkyl, wherein alkyl, alkenyl and cycloalkylare unsubstituted or substituted with one to three substituents selectedfrom halogen, —C₁₋₆alkyl, —OC₁₋₆alkyl, and —CO₂C₁₋₆alkyl. In anotherembodiment of the present invention, each R^(c) is independentlyselected from the group consisting of: hydrogen, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₁₋₆alkyl-OH, —C(O)C₁₋₆alkyl, and SO₂C₁₋₆alkyl, whereinalkyl and alkenyl are unsubstituted or substituted with one to threesubstituents selected from halogen.

In another embodiment of the present invention, each R^(c) isindependently selected from the group consisting of hydrogen,—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₁₋₆alkyl-OH, —C(O)C₁₋₆alkyl, andSO₂C₁₋₆alkyl, wherein alkyl and alkenyl are unsubstituted or substitutedwith one to three F substituents.

In another embodiment of the present invention, each R^(c) isindependently selected from the group consisting of hydrogen andC₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one tothree F substituents. In another embodiment of the present invention,each R^(c) is independently selected from the group consisting ofhydrogen and C₁₋₆alkyl. In another embodiment of the present invention,each R^(c) is independently selected from the group consisting of:hydrogen and CH₃.

In another embodiment of the present invention, R^(c) is hydrogen.

In another embodiment of the present invention, each R^(c) isindependently selected from the group consisting of C₁₋₆alkyl, whereineach alkyl is unsubstituted or substituted with one to three Fsubstituents. In another embodiment of the present invention, each R^(c)is independently selected from the group consisting of C₁₋₆alkyl. Inanother embodiment of the present invention, R^(c) is CH₃.

In another embodiment of the present invention, each R^(d) isindependently selected from the group consisting of hydrogen,—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₁₋₆alkyl-OH, —C₃₋₆cycloalkyl,—C(O)C₁₋₆alkyl, and SO₂C₁₋₆alkyl, wherein alkyl, alkenyl and cycloalkylare unsubstituted or substituted with one to three substituents selectedfrom halogen, —C₁₋₆alkyl, —OC₁₋₆alkyl, and —CO₂C₁₋₆alkyl, or R^(c) andR^(d) together with the nitrogen atom they are attached to form aC₄₋₈cycloheteroalkyl ring, wherein the C₄₋₈cycloheteroalkyl ring isunsubstituted or substituted with 1-4 substituents selected fromhalogen, —C₁₋₆alkyl, —OC₁₋₆alkyl, and —CO₂C₁₋₆alkyl. In anotherembodiment of the present invention, each R^(d) is independentlyselected from the group consisting of hydrogen, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₁₋₆alkyl-OH, —C₃₋₆cycloalkyl, —C(O)C₁₋₆alkyl, andSO₂C₁₋₆alkyl, wherein alkyl, alkenyl and cycloalkyl are unsubstituted orsubstituted with one to three substituents selected from halogen,—C₁₋₆alkyl, —OC₁₋₆alkyl, and —CO₂C₁₋₆alkyl. In another embodiment of thepresent invention, each R^(d) is independently selected from the groupconsisting of: hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₁₋₆alkyl-OH,—C(O)C₁₋₆alkyl, and SO₂C₁₋₆alkyl, wherein alkyl and alkenyl areunsubstituted or substituted with one to three substituents selectedfrom halogen.

In another embodiment of the present invention, each R^(d) isindependently selected from the group consisting of hydrogen andC₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one tothree F substituents. In another embodiment of the present invention,each R^(d) is independently selected from the group consisting ofhydrogen and C₁₋₆alkyl. In another embodiment of the present invention,each R^(d) is independently selected from the group consisting of:hydrogen and CH₃. In another embodiment of the present invention, R^(d)is hydrogen.

In another embodiment of the present invention, each R^(d) isindependently selected from the group consisting of C₁₋₆alkyl, whereinalkyl is unsubstituted or substituted with one to three F substituents.In another embodiment of the present invention, each R^(d) isindependently selected from the group consisting of C₁₋₆alkyl. Inanother embodiment of the present invention, R^(d) is CH₃.

In another embodiment of the present invention, m is 0 or 1. In a classof this embodiment, m is 0. In another class of this embodiment, m is 1.

In another embodiment of the present invention, n is 0, 1, 2 or 3. Inanother class of this embodiment, n is 1, 2, or 3. In another class ofthis embodiment, n is 0, 1, or 2. In another class of this embodiment, nis 1 or 2. In another class of this embodiment, n is 0 or 1. In anotherclass of this embodiment, n is 0 or 2. In another class of thisembodiment, n is 0. In another class of this embodiment, n is 1. Inanother class of this embodiment, n is 2. In another class of thisembodiment, n is 3.

In another embodiment of the present invention, p is 0, 1, 2, 3, 4, 5 or6. In a class of this embodiment, p is 0, 1, 2, 3, or 4. In anotherclass of this embodiment, p is 0, 1, 2, or 3.

In another embodiment of the present invention, p is 1, 2, 3, 4, 5 or 6.In another class of this embodiment, p is 1, 2, 3, or 4. In anotherclass of this embodiment, p is 1, 2, or 3. In another class of thisembodiment, p is 0, 1 or 2. In another class of this embodiment, p is 0or 1. In another class of this embodiment, p is 1 or 2. In another classof this embodiment, p is 0. In another class of this embodiment, p is 1.In another class of this embodiment, p is 2.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ia:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ib:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ic:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Id:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ie:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula If:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ig:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ih:

or a pharmaceutically acceptable salt thereof.

The compound of structural formula I, includes the compounds ofstructural formulas Ia, Ib, Ic, Id, Ie, If, Ig and Ih, andpharmaceutically acceptable salts, hydrates and solvates thereof.

Another embodiment of the present invention relates to compounds ofstructural formula I wherein:

A is selected from the group consisting of:

(1) aryl,

(2) heteroaryl, and

(3) —O-aryl,

wherein aryl and heteroaryl are unsubstituted or substituted with 1-5substituents selected from R^(a);

B is selected from the group consisting of:

(1) aryl, and

(2) heteroaryl,

wherein aryl and heteroaryl are unsubstituted or substituted with 1-4substituents selected from R^(b);

X is selected from the group consisting of:

(1) NR⁷, and

(2) —CR⁸R⁹;

Y is selected from the group consisting of:

(1) NR³, and

(2) —CR¹⁰R¹¹;

R¹ is selected from the group consisting of:

(1) hydrogen,

(2) —C₁₋₆alkyl, and

(3) —(CH₂)_(p)—OH,

wherein CH₂ and alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl;

R² is selected from the group consisting of:

(1) hydrogen,

(2) —C₁₋₆alkyl, and

(3) —(CH₂)_(p)—OH,

wherein CH₂ and alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl, or R¹and R² together with the carbon atom they are attached to form aC₃₋₆cycloalkyl ring, wherein the cycloalkyl ring is unsubstituted orsubstituted with 1-2 substituents selected from: halogen, —C₁₋₆alkyl,and —OC₁₋₆alkyl;R³ is selected from the group consisting of:

(1) hydrogen, and

(2) OH;

R⁴, R⁵, and R⁶ are hydrogen;

R⁷ is selected from the group consisting of:

(1) hydrogen, and

(2) —C₂₋₆alkenyl,

wherein alkenyl is unsubstituted or substituted with 1-2 substituentsselected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl;

R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are hydrogen; and

m is 0 or 1;

or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention relates to compounds ofstructural formula I wherein:

A is selected from the group consisting of:

(1) aryl, and

(2) heteroaryl,

wherein aryl and heteroaryl are unsubstituted or substituted with 1-5substituents selected from R^(a);

B is selected from the group consisting of:

(1) aryl, and

(2) heteroaryl,

wherein aryl and heteroaryl are unsubstituted or substituted with 1-4substituents selected from R^(b);

X is selected from the group consisting of:

(1) NR⁷, and

(2) —CR⁸R⁹;

Y is NR³;

R¹ is selected from the group consisting of:

(1) hydrogen, and

(2) —C₁₋₆alkyl,

wherein alkyl is unsubstituted or substituted with 1-2 substituentsselected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl;

R² is selected from the group consisting of:

(1) hydrogen,

(2) —C₁₋₆alkyl, and

(3) —(CH₂)_(p)—OH,

wherein CH₂ and alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl;

R³ is hydrogen;

R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are hydrogen; and

m is 0 or 1;

or a pharmaceutically acceptable salt thereof.

Illustrative, but non-limiting, examples of the compounds of the presentinvention that are useful as inhibitors of TarO are the followingcompounds:

or pharmaceutically acceptable salts thereof.

Additional illustrative, but non-limiting, examples of the compounds ofthe present invention that are useful as inhibitors of TarO are thefollowing compounds:

or pharmaceutically acceptable salts thereof.

Although the specific stereochemistries described above are preferred,other stereoisomers, including diastereoisomers, enantiomers, epimers,and mixtures of these may also have utility in treating TarO mediateddiseases.

Synthetic methods for making the compounds are disclosed in the Examplesshown below. Where synthetic details are not provided in the examples,the compounds are readily made by a person of ordinary skill in the artof medicinal chemistry or synthetic organic chemistry by applying thesynthetic information provided herein. Where a stereochemical center isnot defined, the structure represents a mixture of stereoisomers at thatcenter. For such compounds, the individual stereoisomers, includingenantiomers, diastereoisomers, and mixtures of these are also compoundsof the invention.

Definitions

“Ac” is acetyl, which is CH₃C(═O)—.

“Alkyl” means saturated carbon chains which may be linear or branched orcombinations thereof, unless the carbon chain is defined otherwise.Other groups having the prefix “alk”, such as alkoxy and alkanoyl, alsomay be linear or branched, or combinations thereof, unless the carbonchain is defined otherwise. Examples of alkyl groups include methyl,ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl,heptyl, octyl, nonyl, and the like.

“Alkenyl” means carbon chains which contain at least one carbon-carbondouble bond, and which may be linear or branched, or combinationsthereof, unless otherwise defined. Examples of alkenyl include vinyl,allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl,2-methyl-2-butenyl, and the like.

“Alkynyl” means carbon chains which contain at least one carbon-carbontriple bond, and which may be linear or branched, or combinationsthereof, unless otherwise defined. Examples of alkynyl include ethynyl,propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.

“Cycloalkyl” means a saturated monocyclic, bicyclic, tricyclic, bridgedor spirocyclic carbocyclic ring, having a specified number of carbonatoms. The term may also be used to describe a carbocyclic ring fused toan aryl group. Examples of cycloalkyl include cyclopropyl, cyclopentyl,cyclohexyl, cycloheptyl, and the like. In one embodiment of the presentinvention, cycloalkyl is selected from: cyclohexane and norbornane. Inanother embodiment of the present invention, cycloalkyl is adamantane.In another embodiment of the present invention, cycloalkyl iscyclopropyl.

“Cycloheteroalkyl” means a saturated or partly unsaturated non-aromaticmonocyclic, bicyclic, tricyclic, bridged or spirocyclic carbocyclic ringor ring system containing at least one ring heteroatom selected from N,NH, S (including SO and SO₂) and O. The cycloheteroalkyl ring may besubstituted on the ring carbons and/or the ring nitrogen(s). Examples ofcycloheteroalkyl include tetrahydrofuran, pyrrolidine,tetrahydrothiophene, azetidine, piperazine, piperidine, morpholine,oxetane and tetrahydropyran. In one embodiment of the present invention,cycloheteroalkyl is selected from: morpholine, pyrrolidine, piperazineand tetrahydrofuran. In another embodiment of the present invention,cycloheteroalkyl is selected from: pyrrolidine and piperidine.

“Aryl” means a monocyclic, bicyclic, tricyclic, bridged or spirocyclicaromatic ring or ring system containing 5-14 carbon atoms, wherein atleast one of the rings is aromatic. The term may also be used todescribe a ring system in which a cycloalkyl and/or cycloheteroalkylring is fused to an aryl group. Examples of aryl include phenyl,naphthyl, and tetrahydronaphthalene. In one embodiment of the presentinvention, aryl is phenyl, naphthalene and tetralin. In anotherembodiment of the present invention, aryl is phenyl, and naphthalene. Inanother embodiment of the present invention, aryl is phenyl. In anotherembodiment of the present invention, aryl is naphthalene. In anotherembodiment of the present invention, aryl is tetralin.

“Heteroaryl” means monocyclic, bicyclic, tricyclic, bridged orspirocyclic ring or ring system containing 5-14 carbon atoms andcontaining at least one ring heteroatom selected from N, NH, S(including SO and SO₂) and O, wherein at least one of the heteroatomcontaining rings is aromatic. The term may also be used to describe aring system in which a cycloalkyl ring and/or a cycloheteroalkyl ring isfused to a heteroaryl group. Examples of heteroaryl include pyrrolyl,isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl,thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl,triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl,benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl,benzothiophenyl, quinolyl, indolyl, isoquinolyl, quinazolinyl,dibenzofuranyl, isoindoline, isoindoline-1-one, benzo[b][1,4]oxazine,2H-benzo[b][1,4]oxazin-3(4H)-one, benzo[d]oxazole.benzo[d]oxazol-2(3H)-one, and the like. In one embodiment of the presentinvention, heteroaryl is selected from: isoquinoline, pyrazolopyridine,naphthyridine, quinoxaline, dihydrobenzo-dioxine or benzodioxane,indole, indazole, thienopyridine, furopyridine, thiazole, quinoline,pyridine, pyrazole, quinazoline, dihydroisoindole,dihydrocyclopentan[b]pyridine, imidazothiazole, dihydropyridooxazine,and benzothiophene. In another embodiment, heteroaryl is selected from:isoindoline-1-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, andbenzo[d]oxazol-2(3H)-one. In another embodiment of the presentinvention, heteroaryl is selected from: isoquinoline,pyrazolo[1,5-a]pyridine, 1,6-naphthyridine, quinoxaline,2,3-dihydro-1,4-benzodioxine or benzodioxane, indole,thieno[3,2-c]pyridine, furo[2.3-c]pyridine, thiazole, quinoline,pyridine, pyrazole, quinazoline, 2,3-dihydroisoindole,6,7-dihydro-5H-cyclopentan[b]pyridine, imidazo[2,1-b][1,3]thiazole,2,3-dihydropyrido[3,2-b][1,4]oxazine, and benzothiophene. In anotherembodiment of the present invention, heteroaryl is selected from:isoquinoline, pyrazolo[1,5-a]pyridine, 1,6-naphthyridine, quinazoline,and benzothiophene. In another embodiment of the present invention,heteroaryl is selected from: isoquinoline, and 1,6-naphthyridine. Inanother embodiment of the present invention, heteroaryl is isoquinoline.In another embodiment of the present invention, heteroaryl ispyrazolo[1,5-a]pyridine. In another embodiment of the present invention,heteroaryl is 1,6-naphthyridine. In another embodiment of the presentinvention, heteroaryl is quinazoline. In another embodiment of thepresent invention, heteroaryl is benzothiophene.

“Halogen” includes fluorine, chlorine, bromine and iodine.

“Me” represents methyl.

When any variable (e.g., R¹, R^(a), etc.) occurs more than one time inany constituent or in formula I, its definition on each occurrence isindependent of its definition at every other occurrence.

Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds. A squiggly line acrossa bond in a substituent variable represents the point of attachment.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, a C₁₋₅ alkylcarbonylamino C₁₋₆ alkyl substituent isequivalent to:

In choosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e. R¹, R², etc.,are to be chosen in conformity with well-known principles of chemicalstructure connectivity and stability.

The term “substituted” shall be deemed to include multiple degrees ofsubstitution by a named substitutent. Where multiple substituentmoieties are disclosed or claimed, the substituted compound can beindependently substituted by one or more of the disclosed or claimedsubstituent moieties, singly or plurally. By independently substituted,it is meant that the (two or more) substituents can be the same ordifferent.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, salts and/or dosage formswhich are, using sound medical judgment, and following all applicablegovernment regulations, safe and suitable for administration to a humanbeing or an animal.

The term “% enantiomeric excess” (abbreviated “ee”) shall mean the %major enantiomer less the % minor enantiomer. Thus, a 70% enantiomericexcess corresponds to formation of 85% of one enantiomer and 15% of theother. The term “enantiomeric excess” is synonymous with the term“optical purity.” Compounds of Formula I may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. The present invention is meant to encompass all suchisomeric forms of the compounds of Formula I.

The independent syntheses of optical isomers and diastereoisomers ortheir chromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the X-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well-known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereoisomeric mixture, followed by separation of the individualdiastereoisomers by standard methods, such as fractional crystallizationor chromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Tautomers are defined as compounds that undergo rapid proton shifts fromone atom of the compound to another atom of the compound. Some of thecompounds described herein may exist as tautomers with different pointsof attachment of hydrogen. Such an example may be a ketone and its enolform known as keto-enol tautomers. The individual tautomers as well asmixtures thereof are encompassed with compounds of Formula I.

In the compounds of general formula I, the atoms may exhibit theirnatural isotopic abundances, or one or more of the atoms may beartificially enriched in a particular isotope having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number predominately found in nature. The present invention ismeant to include all suitable isotopic variations of the compounds ofstructural formula I. For example, different isotopic forms of hydrogen(H) include protium (¹H), deuterium (²H), and tritium (³H). Protium isthe predominant hydrogen isotope found in nature. Enriching fordeuterium may afford certain therapeutic advantages, such as increasingin vivo half-life or reducing dosage requirements, or may provide acompound useful as a standard for characterization of biologicalsamples. Tritium is radioactive and may therefore provide for aradiolabeled compound, useful as a tracer in metabolic or kineticstudies. Isotopically-enriched compounds within structural formula I,can be prepared without undue experimentation by conventional techniqueswell known to those skilled in the art or by processes analogous tothose described in the Schemes and Examples herein using appropriateisotopically-enriched reagents and/or intermediates.

Furthermore, some of the crystalline forms for compounds of the presentinvention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe instant invention may form solvates with water or common organicsolvents. Such solvates are encompassed within the scope of thisinvention.

It is generally preferable to administer compounds of the presentinvention as enantiomerically pure formulations. Racemic mixtures can beseparated into their individual enantiomers by any of a number ofconventional methods. These include chiral chromatography,derivatization with a chiral auxiliary followed by separation bychromatography or crystallization, and fractional crystallization ofdiastereomeric salts.

Salts:

It will be understood that the present invention includes compounds ofthe present invention and the pharmaceutically acceptable salts thereof.The present invention also includes salts that are not pharmaceuticallyacceptable when they are used as precursors to the free compounds ortheir pharmaceutically acceptable salts or in other syntheticmanipulations.

The compounds of the present invention may be administered in the formof a pharmaceutically acceptable salt. The term “pharmaceuticallyacceptable salt” refers to salts prepared from pharmaceuticallyacceptable non-toxic bases or acids including inorganic or organic basesand inorganic or organic acids. Salts of basic compounds encompassedwithin the term “pharmaceutically acceptable salt” refer to non-toxicsalts of the compounds of this invention which are generally prepared byreacting the free base with a suitable organic or inorganic acid.Representative salts of basic compounds of the present inventioninclude, but are not limited to, the following: acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate,pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide and valerate.Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof include, butare not limited to, salts derived from inorganic bases includingaluminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, mangamous, potassium, sodium, zinc, and the like.Particularly preferred are the ammonium, calcium, magnesium, potassium,and sodium salts. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, cyclic amines, and basic ion-exchange resins, such as arginine,betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

Also, in the case of a carboxylic acid (—COOH) or alcohol group beingpresent in the compounds of the present invention, pharmaceuticallyacceptable esters of carboxylic acid derivatives, such as methyl, ethyl,or pivaloyloxymethyl, or acyl derivatives of alcohols, such as O-acetyl,O-pivaloyl, O-benzoyl, and O-aminoacyl, can be employed. Included arethose esters and acyl groups known in the art for modifying thesolubility or hydrolysis characteristics for use as sustained-release orprodrug formulations.

Solvates, and in particular, the hydrates of the compounds of thepresent invention are included in the present invention as well.

Utilities

The compounds of the present invention are TarO inhibitors, and may beuseful to treat diseases that are modulated by TarO inhibitors. Many ofthese diseases are summarized below.

The compounds of the present invention, and pharmaceutically acceptablesalts thereof, may be useful for the treatment, prevention orsuppression of a bacterial infection, including but not limited to, agram negative bacterial infection, a gram-positive bacterial infection,a methicillin-resistant S. aureus (MRSA) bacterial infection, and/or amethicillin-resistant S. epidermidis (MRSE) bacterial infection.

The compounds of the present invention, and pharmaceutically acceptablesalts thereof, may also be useful to sensitize bacteria to a subject'sinnate immune response and enhance bacterial clearance by the subject'simmune system, including but not limited to gram negative bacteria, grampositive bacteria, MRSA bacteria and MRSE bacteria.

Further, the compounds of the present invention, and pharmaceuticallyacceptable salts thereof, in combination with a β-lactam antibiotic, maybe useful for the treatment, prevention or suppression of a bacterialinfection, including but not limited to, a gram-positive bacterialinfection, a methicillin-resistant S. aureus (MRSA) bacterial infection,and/or a methicillin-resistant S. epidermidis (MRSE) bacterialinfection.

Further, the compounds of the present invention, and pharmaceuticallyacceptable salts thereof, may also be useful in combination with aβ-lactam antibiotic, including but not limited to a penicillinantibiotic, a cephamycin antibiotic, a cephalosporin antibiotic or acarbapenem antibiotic, for the treatment of bacterial infections,particularly antibiotic resistant gram negative and/or gram positivebacterial infections such as MRSA infections and/or MRSE infections.

In particular, the compounds of the present invention, andpharmaceutically acceptable salts thereof, may be useful in combinationwith imipenem for the treatment of bacterial infections, particularlyantibiotic resistant gram negative and/or gram positive bacterialinfections such as MRSA infections, and/or MRSE infections.

In particular, the compounds of the present invention, andpharmaceutically acceptable salts thereof, may also be useful incombination with dicloxacillin for the treatment of bacterialinfections, particularly antibiotic resistant gram negative and/or grampositive bacterial infections such as MRSA infections and/or MRSEinfections.

The compounds of the present invention, or pharmaceutically acceptablesalts thereof, alone or in combinations with a β-lactam antibiotic, maybe effective in restoring bacterial susceptibility to treatment with aβ-lactam antibiotic in a subject, including but not limited to,decreasing gram negative susceptibility, gram positive bacterialsusceptibility, methicillin-resistant S. aureus (MRSA) bacterialsusceptibility, and/or methicillin-resistant S. epidermidis (MRSE)bacterial susceptibility.

The compounds of the present invention, or pharmaceutically acceptablesalts thereof, alone or in combinations with a β-lactam antibiotic, mayalso be effective in restoring bacterial susceptibility to treatmentwith a β-lactam antibiotic in a bacterial cell culture, including butnot limited to, decreasing gram negative susceptibility, gram positivebacterial susceptibility, methicillin-resistant S. aureus (MRSA)bacterial susceptibility, and/or methicillin-resistant S. epidermidis(MRSE) bacterial susceptibility.

The compounds of the present invention, or pharmaceutically acceptablesalts thereof, alone or in combinations with a β-lactam antibiotic, maybe effective in decreasing bacterial resistance to treatment with aβ-lactam antibiotic in a subject, including but not limited to,decreasing gram negative bacterial resistance, decreasing gram positivebacterial resistance, methicillin-resistant S. aureus (MRSA) bacterialresistance, and/or methicillin-resistant S. epidermidis (MRSE) bacterialresistance.

The compounds of the present invention, or pharmaceutically acceptablesalts thereof, alone or in combination with a β-lactam antibiotic may beeffective in treating highly resistant infections in a subject,including but not limited to, gram negative bacterial infections, grampositive bacterial infections, methicillin-resistant S. aureus (MRSA)bacterial infections, and/or methicillin-resistant S. epidermidis (MRSE)bacterial infections.

The compounds of the present invention, or pharmaceutically acceptablesalts thereof, alone or in combination with a β-lactam antibiotic may beeffective in increasing β-lactam antibiotic effectiveness to treat abacterial infection in a subject, including but not limited to, a gramnegative bacterial infection, a gram positive bacterial infection, amethicillin-resistant S. aureus (MRSA) bacterial infection, and/or amethicillin-resistant S. epidermidis (MRSE) bacterial infection.

The compounds of the present invention, or pharmaceutically acceptablesalts thereof, in combination with a β-lactam antibiotic may increasebacterial susceptibility to treatment with a β-lactam antibiotic in asubject, wherein the bacteria includes but is not limited to gramnegative bacteria, gram positive bacteria, methicillin-resistant S.aureus (MRSA) bacteria, and/or methicillin-resistant S. epidermidis(MRSE) bacteria.

The compounds of the present invention, or pharmaceutically acceptablesalts thereof, in combination with a β-lactam antibiotic may providebactericidal synergy against bacterial infections in a subject,including but not limited to, gram negative bacterial infections, grampositive bacterial infections, methicillin-resistant S. aureus (MRSA)bacterial infections, and/or methicillin-resistant S. epidermidis (MRSE)bacterial infections.

The compounds of this invention, or pharmaceutically acceptable saltsthereof, alone or in combination with a β-lactam antibiotic, may alsohave utility in lowering the bacterial load in a subject. In particular,the compounds of this invention, or pharmaceutically acceptable saltsthereof, may have utility in lowering the bacterial level in a subject,alone or in combination with imipenem or dicloxacillin.

The compounds of the present invention may be useful for the treatmentor prevention of one or more of the following diseases by administeringa therapeutically effective amount or a prophylactically effectiveamount of the compound of formula I, or a pharmaceutically acceptablesalt thereof, to a patient in need of treatment:

-   -   (1) bacterial infections;    -   (2) gram negative bacterial infections;    -   (3) gram positive bacterial infections;    -   (4) methicillin-resistant S. aureus (MRSA) infections; and    -   (5) methicillin-resistant S. epidermidis (MRSE) infections.

One or more of these diseases may be treated by the administration of atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt thereof, to a patient in need oftreatment. Further, one or more of these diseases may be prevented bythe administration of a prophylactically effective amount of a compoundof the present invention, or a pharmaceutically acceptable salt thereof,to a patient in need of treatment.

The compounds of the present invention may be useful for the treatmentor prevention of one or more of the following diseases by administeringa therapeutically effective or prophylactically effective amount of thecompound of formula I, or a pharmaceutically acceptable salt thereof,and a β-lactam antibiotic, including but not limited to a penicillinantibiotic, a cephamycin antibiotic, a cephalosporin antibiotic or acarbapenem antibiotic, to a patient in need of treatment.

-   -   (1) bacterial infections;    -   (2) gram negative bacterial infections;    -   (3) gram positive bacterial infections;    -   (4) methicillin-resistant S. aureus (MRSA) infections; and    -   (5) methicillin-resistant S. epidermidis (MRSE) infections.

One or more of these diseases may be treated by the administration of atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt thereof, and a β-lactam antibioticselected from: a penicillin antibiotic, a cephamycin antibiotic, acephalosporin antibiotic and a carbapenem antibiotic, to a patient inneed of treatment.

Further, one or more of these diseases may be prevented by theadministration of a prophylactically effective amount of a compound ofthe present invention, or a pharmaceutically acceptable salt thereof,and a β-lactam antibiotic selected from: a penicillin antibiotic, acephamycin antibiotic, a cephalosporin antibiotic and a carbapenemantibiotic, to a patient in need of treatment.

In particular, the compounds of the present invention may also be usefulfor the treatment or prevention of one or more of the following diseasesby administering a therapeutically effective amount or prophylacticallyeffective amount of the compound of formula I, or a pharmaceuticallyacceptable salt thereof, and dicloxacillin to a patient in need oftreatment:

-   -   (1) bacterial infections;    -   (2) gram negative bacterial infections;    -   (3) gram positive bacterial infections;    -   (4) methicillin-resistant S. aureus (MRSA) infections; and    -   (5) methicillin-resistant S. epidermidis (MRSE) infections.

One or more of these diseases may be treated by the administration of atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt thereof, and dicloxacillin, or apharmaceutically acceptable salt or prodrug thereof, to a patient inneed of treatment. Further, one or more of these diseases may beprevented by the administration of a prophylactically effective amountof a compound of the present invention, or a pharmaceutically acceptablesalt thereof, and dicloxacillin, or a pharmaceutically acceptable saltor prodrug thereof, to a patient in need of treatment.

In particular, the compounds of the present invention may also be usefulfor the treatment or prevention of one or more of the following diseasesby administering a therapeutically effective amount or prophylacticallyeffective amount of the compound of formula I, or a pharmaceuticallyacceptable salt thereof, and imipenem to a patient in need of treatment:

-   -   (1) bacterial infections;    -   (2) gram negative bacterial infections;    -   (3) gram positive bacterial infections;    -   (4) methicillin-resistant S. aureus (MRSA) infections; and    -   (5) methicillin-resistant S. epidermidis (MRSE) infections.

One or more of these diseases may be treated by the administration of atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt thereof, and imipenem, or apharmaceutically acceptable salt or prodrug thereof, to a patient inneed of treatment. Further, one or more of these diseases may beprevented by the administration of a prophylactically effective amountof a compound of the present invention, or a pharmaceutically acceptablesalt thereof, and imipenem, or a pharmaceutically acceptable salt orprodrug thereof, to a patient in need of treatment.

The compounds of the present invention, alone or in combination with aβ-lactam antibiotic, may be useful in the following methods oftreatment.

In another embodiment, the present invention relates to a method oftreating or preventing a disorder, condition or disease that isresponsive to the inhibition of TarO in a patient in need thereofcomprising administration of a therapeutically effective amount of acompound according to Claims 1-21, or a pharmaceutically acceptable saltthereof.

In another embodiment, the present invention relates to a method oftreating a bacterial infection in a patient in need of treatmentcomprising the administration to the patient of a therapeuticallyeffective amount of a compound of Claims 1-21, or a pharmaceuticallyacceptable salt thereof. In a class of this embodiment, the bacterialinfection is a methicillin-resistant S. aureus infection or amethicillin-resistant S. epidermidis infection.

In another embodiment, the present invention relates to a method oftreating a bacterial infection in a patient in need of treatmentcomprising the administration to the patient of a therapeuticallyeffective amount of a compound of Claims 1-21, or a pharmaceuticallyacceptable salt thereof, in combination with a β-lactam antibiotic, or apharmaceutically acceptable salt thereof. In a class of this embodiment,the bacterial infection is a methicillin-resistant S. aureus infectionor a methicillin-resistant S. epidermidis infection. In another class ofthis embodiment, the β-lactam antibiotic is imipenem or dicloxacillin.

A method of treating a bacterial infection comprising the administrationof a therapeutically effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof, to a patient in need oftreatment. In one embodiment, the bacterial infection is a gram positivebacterial infection. In another embodiment, the bacterial infection is agram negative bacterial infection. In another embodiment, the bacterialinfection is a MRSA infection. In another embodiment, the bactericalinfection is a MRSE infection.

A method of treating a bacterial infection comprising administration ofa therapeutically effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof, and a therapeuticallyeffective amount of a β-lactam antibiotic, or a pharmaceuticallyacceptable salt thereof, to a patient in need of treatment. In oneembodiment the β-lactam antibiotic is selected from: a penicillinantibiotic, a cephamycin antibiotic, a cephalosporin antibiotic or acarbapenem antibiotic. In another embodiment, the β-lactam antibiotic isselected from: a penicillin antibiotic and a carbapenem antibiotic. Inanother embodiment, the β-lactam antibiotic is a penicillin antibiotic.In a class of this embodiment, the penicillin antibiotic isdicloxacillin. In another embodiment, the β-lactam antibiotic is acarbapenem antibiotic. In a class of this embodiment, the carbapenemantibiotic is imipenem.

A method of treating a gram negative and/or a gram positive bacterialinfection comprising administration of a therapeutically effectiveamount of a compound of formula I, or a pharmaceutically acceptable saltthereof, and a therapeutically effective amount of a 1-lactamantibiotic, or a pharmaceutically acceptable salt thereof, to a patientin need of treatment. In one embodiment the β-lactam antibiotic isselected from: a penicillin antibiotic, a cephamycin antibiotic, acephalosporin antibiotic or a carbapenem antibiotic. In anotherembodiment, the β-lactam antibiotic is selected from: a penicillinantibiotic and a carbapenem antibiotic. In another embodiment, theβ-lactam antibiotic is a penicillin antibiotic. In a class of thisembodiment, the penicillin antibiotic is dicloxacillin. In another classof this embodiment, the bacterial infection is a gram positive bacterialinfection and the penicillin antibiotic is dicloxacillin. In anotherembodiment, the β-lactam antibiotic is a carbapenem antibiotic. In aclass of this embodiment, the carbapenem antibiotic is imipenem. Inanother class of this embodiment, the bacterial infection is a grannegative bacterial infection and a gram positive bacterial infection andthe carbapenem antibiotic is imipenem. In another class of thisembodiment, the bacterial infection is a gran negative bacterialinfection and the carbapenem antibiotic is imipenem. In another class ofthis embodiment, the bacterial infection is a gram positive bacterialinfection and the carbapenem antibiotic is imipenem.

A method of treating MRSA infection comprising administration of atherapeutically effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof, and a therapeuticallyeffective amount of a β-lactam antibiotic, or a pharmaceuticallyacceptable salt thereof, to a patient in need of treatment. In oneembodiment the β-lactam antibiotic is selected from: a penicillinantibiotic, a cephamycin antibiotic, a cephalosporin antibiotic or acarbapenem antibiotic. In another embodiment, the β-lactam antibiotic isselected from: a penicillin antibiotic and a carbapenem antibiotic. Inanother embodiment, the β-lactam antibiotic is a penicillin antibiotic.In a class of this embodiment, the penicillin antibiotic isdicloxacillin. In another embodiment, the β-lactam antibiotic is acarbapenem antibiotic. In a class of this embodiment, the carbapenemantibiotic is imipenem.

A method of treating MRSE infection comprising administration of atherapeutically effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof, and a therapeuticallyeffective amount of a β-lactam antibiotic, or a pharmaceuticallyacceptable salt thereof, to a patient in need of treatment. In oneembodiment the β-lactam antibiotic is selected from: a penicillinantibiotic, a cephamycin antibiotic, a cephalosporin antibiotic or acarbapenem antibiotic. In another embodiment, the β-lactam antibiotic isselected from: a penicillin antibiotic and a carbapenem antibiotic. Inanother embodiment, the β-lactam antibiotic is a penicillin antibiotic.In a class of this embodiment, the penicillin antibiotic isdicloxacillin. In another embodiment, the β-lactam antibiotic is acarbapenem antibiotic. In a class of this embodiment, the carbapenemantibiotic is imipenem.

A method of treating a bacterial infection by sensitizing the bacteriato the subject's immune system response comprising the administration ofa therapeutically effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof, to a patient in need oftreatment. In one embodiment, the bacterial infection is a gram positivebacterial infection. In another embodiment, the bacterial infection is agram negative bacterial infection. In another embodiment, the bacterialinfection is a MRSA infection. In another embodiment, the bactericalinfection is a MRSE infection.

A method of preventing a bacterial infection comprising theadministration of a prophylactically effective amount of a compound offormula I, or a pharmaceutically acceptable salt thereof, to a patientin need of treatment. In one embodiment, the bacterial infection is agram positive bacterial infection. In another embodiment, the bacterialinfection is a gram negative bacterial infection. In another embodiment,the bacterial infection is a MRSA infection. In another embodiment, thebacterical infection is a MRSE infection.

A method of preventing a bacterial infection comprising administrationof a prophylactically effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof, and a prophylacticallyeffective amount of a β-lactam antibiotic, or a pharmaceuticallyacceptable salt thereof, to a patient in need of treatment. In oneembodiment the β-lactam antibiotic is selected from: a penicillinantibiotic, a cephamycin antibiotic, a cephalosporin antibiotic or acarbapenem antibiotic. In another embodiment, the β-lactam antibiotic isselected from: a penicillin antibiotic and a carbapenem antibiotic. Inanother embodiment, the β-lactam antibiotic is a penicillin antibiotic.In a class of this embodiment, the penicillin antibiotic isdicloxacillin. In another embodiment, the β-lactam antibiotic is acarbapenem antibiotic. In a class of this embodiment, the carbapenemantibiotic is imipenem.

A method of preventing a gram negative and/or a gram positive bacterialinfection comprising administration of a prophylactically effectiveamount of a compound of formula I, or a pharmaceutically acceptable saltthereof, and a prophylactically effective amount of a β-lactamantibiotic, or a pharmaceutically acceptable salt thereof, to a patientin need of treatment. In one embodiment the β-lactam antibiotic isselected from: a penicillin antibiotic, a cephamycin antibiotic, acephalosporin antibiotic or a carbapenem antibiotic. In anotherembodiment, the β-lactam antibiotic is selected from: a penicillinantibiotic and a carbapenem antibiotic. In another embodiment, theβ-lactam antibiotic is a penicillin antibiotic. In a class of thisembodiment, the penicillin antibiotic is dicloxacillin. In another classof this embodiment, the bacterial infection is a gram positive bacterialinfection and the penicillin antibiotic is dicloxacillin. In anotherembodiment, the β-lactam antibiotic is a carbapenem antibiotic. In aclass of this embodiment, the carbapenem antibiotic is imipenem. Inanother class of this embodiment, the bacterial infection is a grampositive and/or a gram negative bacterial infection and the carbapenemantibiotic is imipenem. In another class of this embodiment, thebacterial infection is a gram positive bacterial infection and thecarbapenem antibiotic is imipenem. In another class of this embodiment,the bacterial infection is a gram negative bacterial infection and thecarbapenem antibiotic is imipenem.

A method of preventing a MRSA infection comprising administration of aprophylactically effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof, and a prophylacticallyeffective amount of a β-lactam antibiotic, or a pharmaceuticallyacceptable salt thereof, to a patient in need of treatment. In oneembodiment the β-lactam antibiotic is selected from: a penicillinantibiotic, a cephamycin antibiotic, a cephalosporin antibiotic or acarbapenem antibiotic. In another embodiment, the β-lactam antibiotic isselected from: a penicillin antibiotic and a carbapenem antibiotic. Inanother embodiment, the β-lactam antibiotic is a penicillin antibiotic.In a class of this embodiment, the penicillin antibiotic isdicloxacillin. In another embodiment, the β-lactam antibiotic is acarbapenem antibiotic. In a class of this embodiment, the carbapenemantibiotic is imipenem.

A method of preventing a MRSE infection comprising administration of aprophylactically effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof, and a prophylacticallyeffective amount of a β-lactam antibiotic, or a pharmaceuticallyacceptable salt thereof, to a patient in need of treatment. In oneembodiment the β-lactam antibiotic is selected from: a penicillinantibiotic, a cephamycin antibiotic, a cephalosporin antibiotic or acarbapenem antibiotic. In another embodiment, the β-lactam antibiotic isselected from: a penicillin antibiotic and a carbapenem antibiotic. Inanother embodiment, the β-lactam antibiotic is a penicillin antibiotic.In a class of this embodiment, the penicillin antibiotic isdicloxacillin. In another embodiment, the β-lactam antibiotic is acarbapenem antibiotic. In a class of this embodiment, the carbapenemantibiotic is imipenem.

A method of preventing a bacterial infection by sensitizing the bacteriato the patient's immune system response comprising administration of aprophylactically effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof, and a prophylacticallyeffective amount of a β-lactam antibiotic, or a pharmaceuticallyacceptable salt thereof, to a patient in need of treatment. In oneembodiment, the bacterial infection is a gram positive bacterialinfection. In another embodiment the bacterial infection is a gramnegative bacterial infection. In another embodiment, the bacterialinfection is a MRSA infection. In another embodiment, the bactericalinfection is a MRSE infection. In another embodiment the β-lactamantibiotic is selected from: a penicillin antibiotic, a cephamycinantibiotic, a cephalosporin antibiotic or a carbapenem antibiotic. Inanother embodiment, the β-lactam antibiotic is selected from: apenicillin antibiotic and a carbapenem antibiotic. In anotherembodiment, the β-lactam antibiotic is a penicillin antibiotic. In aclass of this embodiment, the penicillin antibiotic is dicloxacillin. Inanother embodiment, the β-lactam antibiotic is a carbapenem antibiotic.In a class of this embodiment, the carbapenem antibiotic is imipenem.

The invention also includes pharmaceutically acceptable salts of thecompounds of formula I, and pharmaceutical compositions comprising thecompounds of formula I, or pharmaceutically acceptable salts thereof,and a pharmaceutically acceptable carrier.

The invention also includes pharmaceutically acceptable salts of thecompounds of formula I, and pharmaceutical compositions comprising thecompounds of formula I, or pharmaceutically acceptable salts thereof, incombination with a β-lactam antibiotic, and a pharmaceuticallyacceptable carrier.

Other embodiments of the present invention include the following:

(a) A pharmaceutical composition comprising an effective amount of acompound of Formula I as defined above, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

(b) The pharmaceutical composition of (a), further comprising aneffective amount of a β-lactam antibiotic.

(c) The pharmaceutical composition of (b), wherein the beta-lactamantibiotic is selected from the group consisting of methicillin,oxacillin, penicillin G, dicloxacillin, naficillin, cefepime, cefoxitin,cefuroxime, imipenem, doripenem, meropenem, and tebipenem.

(d) The pharmaceutical composition of (b), wherein the beta-lactamantibiotic is selected from the group consisting of: imipenem anddicloxacillin.

(e) The pharmaceutical composition of (b), wherein the β-lactamantibiotic is imipenem.

(f) The pharmaceutical composition of (b), wherein the β-lactamantibiotic is dicloxacillin.

(g) A combination of therapeutically effective amounts of a compound ofFormula I as defined above, or a pharmaceutically acceptable saltthereof, and a β-lactam antibiotic.

(h) The combination of (g), wherein the beta-lactam antibiotic isselected from the group consisting of methicillin, oxacillin, penicillinG, dicloxacillin, naficillin, cefepime, cefoxitin, cefuroxime, imipenem,doripenem, meropenem, and tebipenem.

(i) The combination of (g), wherein the beta-lactam antibiotic isselected from the group consisting of imipenem, and dicloxacillin.

(j) The combination of (g), wherein the β-lactam antibiotic is imipenem.

(k) The combination of (g), wherein the β-lactam antibiotic isdicloxacillin.

(l) A method for treating a bacterial infection comprising administeringto a subject in need of such treatment a therapeutically effectiveamount of a compound of Formula I, or a pharmaceutically acceptable saltthereof, optionally in combination with an effective amount of abeta-lactam antibiotic.

(m) A method for treating a bacterial infection comprising administeringto a subject in need of such treatment a therapeutically effectiveamount of the composition of (a), (b), (c), (d), (e), (f), (g), (i), (j)and (k).

(n) A method for treating a bacterial infection comprising administeringto a subject in need of such treatment a therapeutically effectiveamount of the combination (j), and (k).

(o) The method of treating a bacterial infection as set forth in (m), or(n), wherein the bacterial infection is due to gram positive bacteriaand/or gram negative bacteria.

(p) The method of treating a bacterial infection as set forth in (m), or(n), wherein the bacterial infection is due to methicillin-resistant S.aureas (MRSA) or methicillin-resistant S. epidermidis (MRSE).

(q) A method for preventing a bacterial infection comprisingadministering to a subject in need of such treatment a prophylacticallyeffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, optionally in combination with an effectiveamount of a beta-lactam antibiotic.

(r) A method for preventing a bacterial infection comprisingadministering to a subject in need of such treatment a prophylacticallyeffective amount of the composition of (a), (b), (c), (d), (e), (f),(g), (i), (j) and (k).

(s) A method for preventing a bacterial infection comprisingadministering to a subject in need of such treatment a prophylacticallyeffective amount of the combination (j), and (k).

(t) The method of preventing a bacterial infection as set forth in (q),or (r), wherein the bacterial infection is due to gram positive bacteriaand/or gram negative bacteria.

(u) The method of preventing a bacterial infection as set forth in (q),or (r), wherein the bacterial infection is due to methicillin-resistantS. aureas (MRSA) or methicillin-resistant S. epidermidis (MRSE).

The compounds of the present invention, and pharmaceutically acceptablesalts thereof, may also be useful to prevent MRSA and MRSE infections ina subject. For example, TarO inhibitors may be used to coat medicaldevices such as catheters, shunts, and prosthetic devices to preventinfections by preventing the bacteria from forming biofilms.

The present invention also includes a compound of Formula I, or apharmaceutically acceptable salt thereof, (i) for use in, (ii) for useas a medicament for, or (iii) for use in the preparation or manufactureof a medicament for treating bacterial infection. In these uses, thecompounds of the present invention can optionally be employed incombination with one or more β-lactam antibiotics.

The compounds of the present invention may be used for the manufactureof a medicament which may be useful for treating one or more of thesediseases, alone or in combination with a β-lactam antibiotic, includingbut not limited to, a penicillin antibiotic, a cephamycin antibiotic, acephalosporin antibiotic or a carbapenem antibiotic:

-   -   (1) bacterial infections;    -   (2) gram negative bacterial infections;    -   (3) gram positive bacterial infections;    -   (4) methicillin-resistant S. aureus (MRSA) infections; and    -   (4) methicillin-resistant S. epidermidis (MRSE) infections.

The compounds of the present invention may be used for manufacturing amedicament for the treatment of one or more of these diseases incombination with a β-lactam antibiotic, such as a penicillin antibiotic,a cephamycin antibiotic, a cephalosporin antibiotic or a carbapenemantibiotic:

-   -   (1) bacterial infections;    -   (2) gram negative bacterial infections;    -   (3) gram positive bacterial infections;    -   (4) methicillin-resistant S. aureus (MRSA) infections; and    -   (4) methicillin-resistant S. epidermidis (MRSE) infections.

Further, the compounds of the present invention may be used formanufacturing a medicament for the treatment of one or more of thesediseases in combination with a β-lactam antibiotic selected from:imipenem and dicloxacillin:

-   -   (1) bacterial infections;    -   (2) gram negative bacterial infections;    -   (3) gram positive bacterial infections;    -   (4) methicillin-resistant S. aureus (MRSA) infections; and    -   (4) methicillin-resistant S. epidermidis (MRSE) infections.

A compound of formula I of the present invention, or a pharmaceuticallyacceptable salt thereof, may be used in the manufacture of a medicamentfor the treatment of bacterial infections in a human or other mammalianpatient.

A compound of formula I of the present invention, or a pharmaceuticallyacceptable salt thereof, may be used in the manufacture of a medicamentfor the treatment of gram negative bacterial infections in a human orother mammalian patient.

A compound of formula I of the present invention, or a pharmaceuticallyacceptable salt thereof, may be used in the manufacture of a medicamentfor the treatment of gram positive bacterial infections in a human orother mammalian patient.

In particular, a compound of formula I of the present invention, or apharmaceutically acceptable salt thereof, may be used in the manufactureof a medicament for the treatment of MRSA infections in a human or othermammalian patient. In particular, a compound of formula I of the presentinvention, or a pharmaceutically acceptable salt thereof, may be used inthe manufacture of a medicament for the treatment of MRSE infections ina human or other mammalian patient.

Other medical uses of the compounds of the present invention aredescribed herein.

The phrase “treatment of a bacterial infection” means the administrationof a compound of the present invention, or a pharmaceutically acceptablesalt thereof, alone or in combination with another antibiotic, such asbut not limited to a β-lactam antibiotic, to a subject, such as a humanor mammal, infected with bacteria. The phrase “treatment of a bacterialinfection” as used herein includes but is not limited to, treatment of agram negative bacterial infection, treatment of a gram positivebacterial infection, treatment of a MRSA infection, and treatment of aMRSE infection.

The phrase “bacterial infection” means an infection caused by bacteria.

The phrase“gram negative bacterial infection” means an infection causedby gram negative bacteria.

The phrase“gram positive bacterial infection” means an infection causedby gram positive bacteria.

The phrase “MRSA infection” means an infection caused by MRSA bacteria.

The phrase “MRSE infection” means an infection caused by MRSE bacteria.

One outcome of treatment may be killing the bacteria in the bacterialinfection. Another outcome of treatment may be decreasing the number ofbacteria. Another outcome of treatment may be inducing cell death in abacterium, in particular in a gram positive bacterium. Another outcomeof treatment may be reducing the proliferation of bacterium, inparticular gram positive bacterium. Another outcome of treatment may beinducing cell death in a bacterium, in particular in a gram negativebacterium. Another outcome of treatment may be reducing theproliferation of bacterium, in particular gram negative bacterium.Another outcome of treatment may be decreasing bacterial levels in asubject. Another outcome of treatment may be decreasing the bacterialload. Another outcome of treatment may be increasing β-lactam antibioticeffectiveness against the bacteria. Another outcome of treatment may bedecreasing bacterial resistance to β-lactam antibiotics. Another outcomeof treatment may be increasing bacterial susceptibility to treatmentwith β-lactam antibiotics. Another outcome of treatment may be todecrease the viability of the bacteria. Another outcome of treatment maybe to inhibit bacterial growth. Another outcome of treatment may be tokill >95% of the bacteria. Another outcome of treatment may be tokill >80% of the bacteria. Another outcome of treatment may be tokill >50% of the bacteria. Another outcome of treatment may be tokill >20% of the bacteria. Another outcome of treatment may be tokill >10% of the bacteria. Another outcome of treatment may be to killenough bacteria in a subject to enable the subject's immune system tokill the bacteria. Another outcome of treatment may be to sensitizebacteria to the subject's immune system response.

Another outcome of treatment may be achieving the clinical breakpoint ofβ-lactam antibiotics established by CLSI (the Clinical and LaboratoryStandard Institute USA), or the maximum concentration at which aspecific bacterium is designated as susceptible or resistant to theantibiotic. The antibiotic clinical breakpoint definitions aredetermined and published yearly by the Clinical and Laboratory StandardInstitute USA (CLSI). The current clinical breakpoint for imipenem is 4μg/ml for the susceptibility/resistance profile of Staphylococci. Thecurrent clinical breakpoint for dicloxacillin is 8 μg/ml for thesusceptibility/resistance profile of Staphylocci.

Another outcome of treatment may be restoring the efficacy of β-lactamantibiotics against methicillin resistant Staphylococci. Another outcomeof treatment may be restoring the efficacy of imipenem against MRSAand/or MRSE. Another outcome of treatment may be restoring the efficacyof dicloxacillin against MRSA and/or MRSE. Another outcome of treatmentmay be a decrease in the number of symptoms of a bacterial infection.Another outcome of treatment may be the reduction in the duration,severity, or frequency of one or more symptoms of a bacterial infection.

Symptoms of a bacterial infection differ depending on the specificpopulation of gram negative and/or gram positive bacteria present in thesubject and the site (e.g. tissue in the subject) where the bacteria arelocated. General symptoms of a gram negative and/or a gram positivebacterial infection include but are not limited to: fever, swelling,pain, and discharge in the infected area. Additional symptoms mayinclude sore throat, sinus infection, pharyngitis, nasal discharge,headaches, nausea, stomach pain, stomach inflammation, dehydration,peptic ulcer, stomach ulcer, indigestion, meningitis, lethargy, gatigue,stiffness in neck and back, shaking, low blood pressure, redness in theeye, watery or itchy eyes, blurred vision, abdominal cramping, vomiting,weakness, sensory loss, chills, difficulty breathing, chest pain, stuffynose, congestion, increased heartbeat, discomfort, rash, skindiscoloration, strong urge to urinate, burning sensation duringurination, blood in urine, cloudy urine, strong-smelling urine, blacktarry or bloody stools, diarrhea, loss of bowel control, swollen lymphnodes, confusion or disorientation, yeast infection, bacterialbaginosis, sepsis, painful acne, and boils. Additional symptoms ofbacterial infections are known in the art.

The term “bacterial load” means the measurable quantity of bacteria in asubject or patient. The phrase “decreasing bacterial load” includesdecreasing gram negative bacterial load; decreasing gram positivebacterial load; decreasing MRSE bacterial load; and decreasing MRSAbacterial load.

The phrase “increasing β-lactam antibiotic effectiveness” means theability of a compound of the present invention to increase or restorethe ability of β-lactam antibiotics to treat bacterial infections,including but not limited to gram positive bacterial infections, MRSAinfections and MRSE infections, when administered in combination with aβ-lactam antibiotic.

The phrases “increase bacterial susceptibility to treatment with aβ-lactam antibiotic” and “decreasing bacterial resistance to β-lactamantibiotics” mean that when the bacteria is treated with a combinationof a compound of the present invention and a β-lactam antibiotic, lessof the β-lactam antibiotic is required to reach 95% inhibition of thebacteria (or MITC₉₅) than when the β-lactam antibiotic is administeredalone.

The phrase “decreasing bacterial resistance to β-lactam antibiotics”includes decreasing gram negative bacteria resistance to β-lactamantibiotics; decreasing gram positive bacteria resistance to β-lactamantibiotics; decreasing MRSE resistance to β-lactam antibiotics; anddecreasing MRSA resistance to β-lactam antibiotics.

The term “antibiotic” refers to a compound or composition whichdecreases the viability of a microorganism or bacteria, or whichinhibits the growth or proliferation of a microorganism or bacteria. Thephrase “inhibits the growth or proliferation” means increasing thegeneration time (i.e., the time required for the bacterial cell todivide or for the population to double).

The terms “beta-lactam antibiotic” and “β-lactam antibiotic” refer to acompound with antibiotic properties that contains a beta-lactam ring intheir molecular structures. β-lactam antibiotics that may be suitablefor use in combination with the compounds of the present inventioninclude, but are not limited to: penicillin antibiotics, cephamycinantibiotics, cephalosporin antibiotics, and carbapenem antibiotics.

The terms “MRSA infection” as used herein means a methicillin-resistantStaphylococcus aureus infection.

The terms “MRSE infection” as used herein means a methicillin-resistantStaphylococcus epidermidis infection.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual or mammal in need oftreatment. Administration includes providing the compound of theinvention or a prodrug of a compound of the invention to the individualor mammal in need of treatment, alone or in combination with a β-lactam.

The administration of the compound of structural formula I in order topractice the present methods of therapy is carried out by administeringan effective amount of the compound of structural formula I to themammal in need of such treatment or prophylaxis. The need for aprophylactic administration according to the methods of the presentinvention is determined via the use of well known risk factors. Theeffective amount of an individual compound is determined, in the finalanalysis, by the physician or veterinarian in charge of the case, butdepends on factors such as the exact disease to be treated, the severityof the disease and other diseases or conditions from which the patientsuffers, the chosen route of administration other drugs and treatmentswhich the patient may concomitantly require, and other factors in thephysician's judgment.

The usefulness of the present compounds in these diseases or disordersmay be demonstrated in animal disease models that have been reported inthe literature.

Administration and Dose Ranges

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dose of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, intravenous, and the like may be employed.Dosage forms include tablets, troches, dispersions, suspensions,solutions, capsules, creams, ointments, aerosols, and the like.Preferably compounds of the present invention are administered orally.

In the treatment or prevention of conditions which require inhibition ofTarO activity, an appropriate dosage level will generally be about 0.01to 500 mg per kg patient body weight per day which can be administeredin single or multiple doses. Preferably, the dosage level will be about0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kgper day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg perday. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to50 mg/kg per day. For oral administration, the compositions arepreferably provided in the form of tablets containing 1.0 to 1000 mg ofthe active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0,50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0,750.0, 800.0, 900.0, and 1000.0 mg of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds may be administered on a regimen of 1, 2, 3, 4, 5 or 6 timesper day, preferably 1, 2, 3, or 4 times a day, more preferably once ortwice per day. The compounds may be administered for 1 day to 28 days,or longer until the bacterial infection is treated or prevented.

The compounds of the present invention may be administered intravenouslyas shots or vaccinations. Intravenous administration of a compound ofthe present invention can be conducted by reconstituting a powdered formof the compounds with an acceptable solvent. Suitable solvents include,for example, saline solutions (e.g. 90% sodium chloride injection) andsterile water (e.g. Sterile Water for Injection, Bacteriostatic Waterfor Injection with methylparaben and propylparaben). The powdered formof the compound can be obtained by lyophilization of a solution of thecompound, after which the powder can be stored (e.g. in a sealed vial)at or below room temperature until it is reconstituted. Theconcentration of the compound in the reconstituted IV solution can be,for example, in a range of from about 0.1 mg/mL to about 20 mg/mL.

For intravenous administration, the compositions are preferably providedin the form of an intravenous (IV) solution containing 1.0 to 1000 mg ofthe active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0,50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0,750.0, 800.0, 900.0, and 1000.0 mg of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Theintravenous solution may be administered on a regimen of 1, 2, 3, 4, 5or 6 times per day, preferably 1, 2, 3, or 4 times a day, morepreferably once or twice per day. The compounds may be administered for1 day to 28 days, or longer until the bacterial infection is treated orprevented.

When treating or preventing bacterial infections, including but notlimited to MRSA and MRSE, or other diseases for which compounds of thepresent invention are indicated, generally satisfactory results areobtained when the compounds of the present invention are administered ata daily dosage of from about 0.01 mg to about 500 mg per kilogram ofanimal body weight, preferably given as a single daily dose or individed doses two to six times a day, or in sustained release form. Thisdosage regimen may be adjusted to provide the optimal therapeuticresponse.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

The compounds of this invention may be used in pharmaceuticalcompositions comprising (a) the compound(s) or pharmaceuticallyacceptable salts thereof, and (b) a pharmaceutically acceptable carrier.The compounds of this invention may be used in pharmaceuticalcompositions that include one or more other active pharmaceuticalingredients. The compounds of this invention may also be used inpharmaceutical compositions in which the compound of the presentinvention or a pharmaceutically acceptable salt thereof is the onlyactive ingredient.

The term “composition,” as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of the present invention and apharmaceutically acceptable carrier.

Combinations

Compounds of the present invention may be used in combination with otherdrugs that may also be useful in the treatment or amelioration of thediseases or conditions for which compounds of the present invention areuseful. Such other drugs may be administered, by a route and in anamount commonly used therefor, contemporaneously or sequentially with acompound of the present invention. In the treatment of patients who havebacterial infections, including but not limited to antibiotic resistantgram negative bacterial infections, gram positive bacterial infections,MRSA infections and MRSE infections, and co-morbidities that accompanythese diseases, more than one drug is commonly administered. Thecompounds of this invention may generally be administered to a patientwho is already taking one or more other drugs for these conditions.Often the compounds will be administered to a patient who is alreadybeing treated with one or more antibiotic compounds, or in combinationwith one or more antibiotics, such as β-lactam antibiotics, when thepatient's bacterial levels are not adequately responding to treatment.

When a compound of the present invention is used contemporaneously withone or more other drugs, a pharmaceutical composition in unit dosageform containing such other drugs and the compound of the presentinvention is preferred. However, the combination therapy also includestherapies in which the compound of the present invention and one or moreother drugs are administered on different overlapping schedules. It isalso contemplated that when used in combination with one or more otheractive ingredients, the compound of the present invention and the otheractive ingredients may be used in lower doses than when each is usedsingly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of the present invention.

It is generally advantageous to use a compound of Formula I in admixtureor conjunction with a beta-lactam antibiotic, such as a carbapenemantibiotic, a penicillin antibiotic, a cephalosporin antibiotic, acephamycin antibiotic, or another β-lactam antibiotic, or a prodrugthereof. The compound of Formula I and the β-lactam antibiotic can beadministered separately (at the same time or as different times) or inthe form of a single composition containing both active ingredients.

Examples of beta-lactam antibiotics that may be administered, separatelyor in the same pharmaceutical composition, in combination with acompound of the formulas described herein include, but are not limitedto:

-   -   (1) penicillin antibiotics, including but not limited to,        methicillin, oxacillin, penicillin G, dicloxacillin and        naficillin;    -   (2) cephamycin antibiotics, including but not limited to,        cefepime and cefoxitin; (3) cephalosporin antibiotics, including        but not limited to, cefuroxime, ceftiofur and cefquinome; and    -   (4) carbapenem antibiotics, including but not limited to,        imipenem, doripenem, meropenem, and tebipenem.

Other suitable beta-lactam antibiotics that may be administered incombination with a compound of the present invention, and eitheradministered separately or in the same pharmaceutical composition aresummarized below.

Carbapenem antibiotics suitable for co-administration with compounds ofthe present invention include imipenem, meropenem, doripenem, tebipenem,biapenem,(4R,5S,6S)-3-[3S,5S)-5-(3-carboxyphenyl-carbamoyl)pyrrolidin-3-ylthio]-6-(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid,(1S,5R,6S)-2-(4-(2-(((carbamoylmethyl)-1,4-diazoniabicyclo[2.2.2]oct-1-yl)-ethyl(1,8-naphthosultam)methyl)-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylatechloride, BMS181139([4R-[4alpha,5beta,6beta(R*)]]-4-[2-[(aminoiminomethyl)amino]ethyl]-3-[(2-cyanoethyl)thio]-6-(1-hydroxyethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid), BO2727 ([4R-3[3S*,5S*(R*)],4alpha,5beta,6beta(R*)]]-6-(1-hydroxyethyl)-3-[[5-[1-hydroxy-3-(methylamino)propyl]-3-pyrrolidinyl]thio]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid monohydrochloride), E1010((1R,5S,6S)-6-[1(R)-hydroxymethyl]-2-[2(S)-[1(R)-hydroxy-1-[pyrrolidin-3(R)-yl]methyl]pyrrolidin-4(S)-ylsulfanyl]-1-methyl-1-carba-2-penem-3-carboxylicacid hydrochloride) and S4661((1R,5S,6S)-2-[(3S,5S)-5-(sulfamoylaminomethyl)pyrrolidin-3-yl]thio-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylicacid),(1S,5R,6S)-1-methyl-2-{7-[4-(aminocarbonylmethyl)-1,4-diazoniabicyclo(2.2.2)octan-1yl]-methyl-fluoren-9-on-3-yl}-6-(1R-hydroxyethyl)-carbapen-2-em-3carboxylate chloride.

Penicillin antibiotics suitable for co-administration with compounds ofthe present invention include dicloxacillin, methicillin, oxacillin,penicillin G, naficillin, benzylpenicillin, phenoxymethylpenicillin,carbenicillin, azidocillin, propicillin, ampicillin, amoxicillin,epicillin, ticarcillin, cyclacillin, pirbenicillin, azlocillin,mezlocillin, sulbenicillin, piperacillin, and other known penicillins.The penicillins may be used in the form of pro-drugs thereof; forexample as in vivo hydrolysable esters, for example the acetoxymethyl,pivaloyloxymethyl, α-ethoxycarbonyloxy-ethyl and phthalidyl esters ofampicillin, benzylpenicillin and amoxicillin; as aldehyde or ketoneadducts of penicillins containing a 6-α-aminoacetamido side chain (forexample hetacillin, metampicillin and analogous derivatives ofamoxicillin); and as esters of carbenicillin and ticarcillin, forexample the phenyl and indanyl α-esters.

Cephalosporin antibiotics suitable for co-administration with compoundof the present invention include cefuroxime, cefatrizine, cephaloridine,cephalothin, cefazolin, cephalexin, cephacetrile, cephapirin,cephamandole nafate, cephradine, 4-hydroxycephalexin, cephaloglycin,cefoperazone, cefsulodin, ceftazidime, cefmetazole, cefotaxime,ceftriaxone, ceftiofur and cefquinome; and other known cephalosporins,all of which may be used in the form of pro-drugs thereof.

Cephamycin antibiotics suitable for co-administration with compound ofthe present invention include cefepime, cefoxitin, cefotetan andcefmetazole, all of which may be used in the form of pro-drugs thereof.

In one embodiment, the antibiotic co-administered with a compound of thepresent invention is selected from: imipenem and dicloxacillin.

In another embodiment, the antibiotic co-administered with a compound ofthe present invention is a carbapenem antibiotic selected from:imipenem, meropenem, doripenem and tebipenem.

In another embodiment, the antibiotic co-administered with a compound ofthe present invention is a penicillin antibiotic selected from:methicillin, oxacillin, penicillin G, dicloxacillin, naficillin,ampicillin, amoxicillin, carbenicillin, piperacillin, azlocillin,mezlocillin, and ticarcillin, or pharmaceutically acceptable saltsthereof. In another embodiment, the antibiotic co-administered with acompound of the present invention is a penicillin antibiotic selectedfrom: methicillin, oxacillin, penicillin G, dicloxacillin, andnaficillin, or pharmaceutically acceptable salts thereof. Suchpenicillins can optionally be used in the form of their pharmaceuticallyacceptable salts, for example their sodium salts. Ampicillin oramoxicillin can alternatively be employed in the form of fine particlesof the zwitterionic form (generally as ampicillin trihydrate oramoxicillin trihydrate) for use in an injectable or infusablesuspension. In an aspect of this embodiment, the penicillinco-administered with a compound of the present invention is amoxicillin,optionally in the form of its sodium salt or the trihydrate.

In another embodiment, the antibiotic co-administered with a compound ofthe present invention is a cephalosporin antibiotic selected from:cefuroxime, cefotaxime, ceftriaxone and ceftazidime, or apharmaceutically acceptable salts thereof. In another embodiment, theantibiotic co-administered with a compound of the present invention isthe cephalosporin antibiotic cefuroxime, or a pharmaceuticallyacceptable salt thereof.

In another embodiment, the antibiotic co-administered with a compound ofthe present invention is a cephamycin antibiotic selected from:cefepime, cefoxitin, cefotetan and cefmetazole, all of which may be usedin the form of pro-drugs thereof. In another embodiment, the antibioticco-administered with a compound of the present invention is a cephamycinantibiotic selected from: cefepime and cefoxitin, all of which may beused in the form of pro-drugs thereof.

The compounds of the present invention, or pharmaceutically acceptablesalts thereof, in combination with a β-lactam antibiotic, including butnot limited to imipenem and dicloxacillin, may provide bactericidalsynergy in treating bacterial infections in a subject. Whenco-administered with a β-lactam antibiotic, the combination of thecompound of the invention and the β-lactam antibiotic can provide asynergistic bactericical effect.

The terms “synergistic bactericidal effect” and “bactericidal synergy”indicate that the bactericidal effect produced when a β-lactamantibiotic is administered in combination with a compound of the presentinvention is greater than the bactericidal effect produced when theβ-lactam antibiotic is administered alone, or when a compound of thepresent invention is administered alone. The “synergistic bactericidaleffect” and “bactericidal synergy” may represent a significant reductionin minimum inhibition concentration (MIC) values for a beta-lactam as asingle agent. As a result, less β-lactam antibiotic is required to reach95% inhibition (MITC₉₅) of the bacteria when used in combination with acompound of the present invention. The term bactericidal effect includesbut is not limited to bacteria death or the amount of bacteria killed.

The compositions and combinations of the present invention are suitablyadministered in therapeutically effective amounts. The term“therapeutically effective amount” as used herein means that amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal or human that is beingsought by a researcher, veterinarian, medical doctor or other clinician.In one embodiment, the effective amount is a “therapeutically effectiveamount” for the alleviation of the symptoms of the disease or conditionbeing treated (e.g., bacterial infection and/or bacterial drugresistance). In another embodiment, the effective amount is a“prophylactically effective amount” for prophylaxis of the symptoms ofthe disease or condition being prevented (e.g., bacterial infectionand/or bacterial drug resistance. The term “therapeutically effectiveamount” also includes herein the amount of active compound sufficient todecrease the bacterial level in a subject and thereby elicit theresponse being sought (i.e., an “inhibition effective amount”). When theactive compound (i.e., active ingredient) is administered as the salt,references to the amount of active ingredient are to the free acid orfree base form of the compound.

The term “drug resistance” refers to the loss of susceptibility of adrug target, such as bacteria, to drug treatment. The term “resistance”refers to the decrease or loss of inhibitory effect of the drug on thetarget bacteria.

The present invention also includes a method for inhibiting bacterialgrowth comprising administering to a bacterial cell culture, or to abacterially infected cell culture, tissue, or organism, an inhibitioneffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, alone or in combination with a β-lactamantibiotic. The method can involve administration of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, alone or incombination with a β-lactam antibiotic, to an experimental cell culturein vitro to prevent the growth of β-lactam resistant bacteria. Themethod can alternatively involve administration of a compound of FormulaI, or a pharmaceutically acceptable salt thereof, alone or incombination with a β-lactam antibiotic, to a subject including apatient, human or mammal, to prevent or inhibit the growth of β-lactamresistant bacteria in vivo, or to kill β-lactam resistant bacteria invivo. In these cases the compound of Formula I is typicallyco-administered with a β-lactam antibiotic.

Compounds of the invention, or a pharmaceutically acceptable saltthereof, alone or in combination with a β-lactam antibiotic, may beemployed for the treatment, prevention, prophylaxis or inhibition ofbacterial growth or infections due to bacteria that are resistant toβ-lactam antibiotics.

More particularly, the bacteria may be β-lactamase positive strains thatare highly resistant to β-lactam antibiotics. The terms “slightlyresistant” and “highly resistant” are well-understood by those ofordinary skill in the art (see, e.g., Payne et al., Antimicrobial Agentsand Chemotherapy 38:767-772 (1994); Hanaki et al., Antimicrobial Agentsand Chemotherapy 30:11.20-11.26 (1995)).

Compounds of the invention may be useful in combination with antibioticagents for the treatment of infections caused by Class C-β-lactamaseproducing strains, in addition to those infections which are subsumedwithin the antibacterial spectrum of the antibiotic agent.

Examples of class C-β-lactamase producing bacteria are Pseudomonasaeruginosa, Enterobacter cloacae, Klebsiella pneumoniae, Escherichiacoli and Acinetobacter baumannii.

The present invention also provides a method for the treatment orprevention of a TarO mediated disease, which method comprisesadministration to a patient in need of such treatment or at risk ofdeveloping a TarO mediated disease of an amount of a compound of formulaI, or a pharmaceutically acceptable salt thereof, and an amount of oneor more active ingredients, such that together they give effectiverelief.

In a further aspect of the present invention, there is provided apharmaceutical composition comprising a compound of formula I, or apharmaceutically acceptable salt thereof, and one or more activeingredients, together with at least one pharmaceutically acceptablecarrier or excipient.

Thus, according to a further aspect of the present invention there isprovided the use of a compound of formula I, or a pharmaceuticallyacceptable salt thereof, and one or more active ingredients for themanufacture of a medicament for the treatment or prevention of a TarOmediated disease. In a further or alternative aspect of the presentinvention, there is therefore provided a product comprising a compoundof formula I, or a pharmaceutically acceptable salt thereof, and one ormore active ingredients as a combined preparation for simultaneous,separate or sequential use in the treatment or prevention of a TarOmediated disease. Such a combined preparation may be, for example, inthe form of a twin pack.

It will be appreciated that for the treatment or prevention of bacterialinfections, gram negative bacterial infections, gram positive bacterialinfections, MRSA infections, MRSE infections, and related bacterialinfections, a compound of formula I, or a pharmaceutically acceptablesalt thereof, may be used in conjunction with another pharmaceuticalagent effective to treat the bacterial infection.

The present invention also provides a method for the treatment orprevention of bacterial infections, gram negative bacterial infections,gram positive bacterial infections, MRSA infections, MRSE infections,and related bacterial infections, which method comprises administrationto a patient in need of such treatment an amount of compound of formulaI, or a pharmaceutically acceptable salt thereof, and an amount ofanother pharmaceutical agent effective to treat that bacterialinfection, such that together they give effective relief.

The present invention also provides a method for the treatment orprevention of bacterial infections, gram negative bacterial infections,gram positive bacterial infections, MRSA infections, MRSE infections,and related bacterial infections, which method comprises administrationto a patient in need of such treatment an amount of a compound offormula I, or a pharmaceutically acceptable salt thereof, and an amountof a β-lactam antibiotic useful in treating that particular bacterialinfection, such that together they give effective relief.

The compounds of formula I, or a pharmaceutically acceptable saltthereof, may be useful in combination with β-lactam antibiotics, suchas, but not limited to, imipenem and dicloxacillin, for the treatment ofbacterial infections, particularly antibiotic resistant gram negativebacterial infections and/or gram positive bacterial infections such asmethicillin-resistant Staphylocuccus aureus (MRSA) infections.

The term “therapeutically effective amount” means the amount thecompound of structural formula I that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician, which includes alleviation of the symptoms of the disorderbeing treated. In one embodiment, the therapeutically effective amountas used herein means that amount of the compound of the presentinvention that alleviates the symptoms of the bacterial infection orbacterial drug resistance when administered alone or in combination witha beta-lactam antibiotic.

The novel methods of treatment and prevention of this invention are fordisorders known to those skilled in the art. The term “patient” as usedherein means a human or mammal. The term “subject” as used herein meansa human, mammal or cell. The term “mammal” includes humans, companionanimals such as dogs and cats, and livestock such as cattle, swine andpoultry. The term cell includes cells in a cell culture.

The weight ratio of the compound of the Formula I to the second activeingredient may be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used. Thus, forexample, when a compound of the Formula I is combined with a beta-lactamantibiotic the weight ratio of the compound of the Formula I to thebeta-lactam antibiotic will generally range from about 1000:1 to about1:1000, preferably about 200:1 to about 1:200. Combinations of acompound of the Formula I and other active ingredients will generallyalso be within the aforementioned range, but in each case, an effectivedose of each active ingredient should be used.

Methods of Synthesis of the Compounds of the Present Invention:

The following reaction schemes and Examples illustrate methods which maybe employed for the synthesis of the compounds of structural formula Idescribed in this invention. These reaction schemes and Examples areprovided to illustrate the invention and are not to be construed aslimiting the invention in any manner. All substituents are as definedabove unless indicated otherwise. Several strategies based uponsynthetic transformations known in the literature of organic synthesismay be employed for the preparation of the compounds of structuralformula I. The scope of the invention is defined by the appended claims.

The compounds of the present invention can be prepared according to theprocedures of the following Examples, using appropriate materials. Thecompounds illustrated in the examples are not, however, to be construedas forming the only genus that is considered as the invention. TheExamples further illustrate details for the preparation of the compoundsof the present invention. Those skilled in the art will readilyunderstand that known variations of protecting groups, as well as of theconditions and processes of the following preparative procedures, can beused to prepare these compounds. It is also understood that whenever achemical reagent such as a boronic acid or a boronate is notcommercially available, such a chemical reagent can be readily preparedfollowing one of numerous methods described in the literature. Alltemperatures are degrees Celsius unless otherwise noted. Mass spectra(MS) were measured either by electrospray ion-mass spectroscopy (ESMS)or by atmospheric pressure chemical ionization mass spectroscopy (APCI).

Abbreviations

Ac is acetyl; AcCN is acetonitrile; AcO is acetoxy; Alk is alkyl;Al(OiPr)₃ is aluminum triisopropoxide; APCI is atmospheric pressurechemical ionization; aq or aq. is aqueous; Ar is aryl; Boc istert-butoxycarbonyl; Br is broad; t-BuOK is potassium tert-butoxide; °C. is degrees celsius; Cbz is benzyloxycarbonyl; CH₂Cl₂ isdichloromethane; CO is carbon monoxide; conc or conc. is concentrated; dis doublet; DAST is (diethylamino)sulfur trifluoride; DBU is1,8-diazabicyclo[5.4.0]undec-7-ene; DIAD is diisopropylazodicarboxylate; DCM is dichloromethane; DIEA and DIPEA areN,N-diisopropylethylamine; DMAP is 4-dimethylaminopyridine; DMF isN,N-dimethylformamide; DMSO is dimethylsulfoxide; dppf is1,1′-Bis(diphenyl-phosphino)ferrocene; EDC and EDC1 are1-ethyl-3-(3-dimethylamino-propyl)carbodiimide; ESI is electrosprayionization; EA or EtOAc is ethyl acetate; Et is ethyl; EtMgBr is ethylmagnesium bromide; EtOH is ethanol; g is gram(s); h or hr or hrs ishour(s); HPLC is high pressure liquid chromatography; HOAc or AcOH isacetic acid; iPrMgCl is isopropyl magnesium chloride; IPA and iPrOH areisopropanol; kg is kilogram(s); KOH ispotassium hydroxide; KOAc ispotassium acetate; L is liter; LC-MS is liquid chromatography-massspectroscopy; LDA is lithium diisopropyl amide; LiOH is lithiumhydroxide; m is multiplet; m-CPBA, MCPBA, or mCPBA is metachloroperbenzoic acid; mL or ml is milliliter; min or mins is minute(s);mol is mole(s); mmol is mmole(s); mg is milligram(s); Mel is methyliodide; MeCN is acetonitrile; MeMgBr is methyl magnesium bromide; MeOHis methyl alcohol; MgSO₄ is magnesium sulfate; MS is mass spectroscopy;MsCl or Ms-Cl is methane sulfonyl chloride; N is normal; Na(AcO)₃BH issodium triacetoxy borohydride; NaHMDS is sodium hexamethyldisilazide;NaOH is sodium hydroxide; Na₂SO₄ is sodium sulfate; NH₄OAc is ammoniumacetate; NBS is N-bromo succinamide; NIS is N-iodo succinamide;HNMe(OMe)HCl is N-methoxy-N-methylamine hydrochloride salt; NMM isN-methyl morpholine; NMO is 4-methyl morpholine N-oxide; NMP is1-methyl-2-pyrrolidinone; NMR is nuclear magnetic resonancespectroscopy; PE is petroleum ether; PG is protecting group; P(Cy)₃ istricyclohexyl phosphine; Pd(Ph₃)₄ istetrakis(triphenylphosphine)-palladium(O); Pd₂(dba)₃ istris(dibenzylideneacetone)-dipalladium(0); Pd[P(t-Bu)₃]₂ isbis(tri-tert-butylphosphine)palladium (0); Pd(dppf)Cl₂ is[1,1′-bis(diphenylphosphino)ferrocene]-dichloro-palladium (II); PMB ispara-methoxybenzyl; PMBCl is para-methoxybenzyl chloride; prep ispreparative; prep. TLC or prep-TLC, or prep TLC is preparative thinlayer chromatography; RBF is round bottom flask; RCM is ring closingmetathesis reaction; rt or r.t. or RT is room temperature; s is singlet;SFC is supercritical fluid chromatography; s-phos is2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl; t is triplet; TBDMSClis tert-butyldimethyl silyl chloride; TBTU isN,N,N′,N′-Tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate;TEA is triethyl amine; THF is tetrahydrofuran; Ti(OiPr)₄ is titaniumisopropoxide; TFA is trifluoroacetic acid; TLC is thin-layerchromatography; TMSCl is trimethyl silyl chloride; TsCl or TosCl isp-toluene sulfonyl chloride; TsOH is p-toluenesulfonic acid, and xphosis 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare either commercially available or made by known procedures in theliterature or as illustrated. The present invention further providesprocesses for the preparation of compounds of structural formula I asdefined above. In some cases the order of carrying out the foregoingreaction schemes may be varied to facilitate the reaction or to avoidunwanted reaction products. The following examples are provided for thepurpose of illustration only and are not to be construed as limitationson the disclosed invention.

All temperatures are degrees Celsius unless otherwise noted.

Example 1(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-N-(isoquinolin-4-ylmethyl)-4-methyl-2-oxooxazolidine-3-carboxamide

Step 1: Benzyl(S)-(1-(3,5-bis(trifluoromethyl)phenyl)-1-oxopropan-2-yl)carbamate

To a solution of 1-bromo-3,5-bis(trifluoromethyl)benzene (10.0 g, 34mmol, 1 eq) and benzyl (S)-(1(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (10.8 g, 40 mmol, 1.2eq) in THF (100 mL) at −10° C. was added dropwise i-PrMgCl (85 mL, 1 Min THF, 85 mmol, 2.5 eq). After the addition, the reaction mixture wasstirred at rt for 12 h. Then the reaction mixture was added slowly intoa solution of 1 N HCl (190 mL) at 0° C. The resulting solution wasextracted with EtOAc (150 mL×3), and the combined EtOAc extracts weredried, and evaporated to give the title compound, which was used in thenext step without further purification.

Step 2:(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one

To a mixture of benzyl(S)-(1-(3,5-bis(trifluoromethyl)phenyl)-1-oxopropan-2-yl)carbamate (16.0g, 38 mmol, 1 eq) and i-PrOH (22.0 g, 418 mmol, 11 eq) in toluene (60mL) was added Al(OiPr)₃ (6.2 g, 34 mmol). After the addition, thereaction mixture was stirred at 40-50° C. for 12 h. The reaction mixturewas cooled to rt, then 50% KOH (3.9 g in 3.9 g of H₂O) was added. Theresulting mixture was stirred at 20° C. for 3 h and then quenched withbrine (100 mL) and extracted with EtOAc (100 mL×2). The combined organiclayers were washed with brine (100 mL×4) and dried. The crude productwas purified by flash chromatography (0% to 100% EtOAc in hexane) toprovide the title compound.

Step 3:(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidine-3-carbonylchloride

To a solution of(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one (8.0g, 26.1 mmol) in THF (50 mL) was added n-butyllithium (10.4 mL, 2.5 M inhexane, 26.1 mmol) slowly at −78° C. The resulting mixture was stirredat −78° C. for 20 min. Then trichloromethyl carbonochloridate (3.2 mL,26.1 mmol) was added rapidly. The reaction mixture was stirred for 30min, and then allowed to warm to rt. The reaction mixture was evaporatedto obtain the title compound, which was used in next step withoutfurther purification.

Step 4:(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-N-(isoquinolin-4-methyl)-4-methyl-2-oxooxazolidine-3-carboxamide

To a solution of(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidine-3-carbonylchloride (64.0 mg, 0.17 mmol) in DCM (1 mL) was added a solution ofisoquinolin-4-yl methanamine (93.0 mg, 0.34 mmol) and triethylamine(0.19 mL, 1.38 mmol) in DCM (1 mL). The resulting mixture was stirred atrt for 12 h, then quenched with water, extracted with DCM, and dried.The resulting residue was purified by flash chromatography (5% to 50%EtOAc in hexane) to obtain the title compound. LC-MS m/z [M+H]⁺ 498 47(calc'd 498 39)

TABLE 1 The compounds in Examples 2-49 were prepared according to theprocedure of Example 1. Calc'd Observed Example Mass Mass NumberStructure Name M + H⁺ M + H⁺ 2

(4S,5R)-5-[3,5- bis(trifluoromethyl)phenyl]- 4-methyl-2-oxo-N-(pyrazolo[1,5- a]pyridin-7-ylmethyl)- 1,3-oxazolidine-3- carboxamide487.11 487.10 3

(4S,5R)-5-[3-fluoro-5- (trifluoromethyl)phenyl]- 4-methyl-N-(2-nitrobenzyl)-2-oxo-1,3- oxazolidine-3- carboxamide 442.10 442.16 4

(4S,5R)-5-[3,5- bis(trifluoromethyl)phenyl]- 4-methyl-N-(1,6-naphthyridin-8- ylmethyl)-2-oxo-1,3- oxazolidine-3- carboxamide 499.38499.68 5

(4S,5R)-N-[2- (difluoromethoxy) benzyl]-5-[3-fluoro-5-(trifluoromethyl)phenyl]- 4-methyl-2-oxo-1,3- oxazolidine-3- carboxamide463.11 463.08 6

(4S,5R)-5-[3-fluoro-5- (trifluoromethyl)phenyl]- 4-methyl-N-(naphthalen-1- ylmethyl)-2-oxo-1,3- oxazolidine-3- carboxamide 447.39447.09 7

(4S,5R)-5-[3-fluoro-5- (trifluoromethyl)phenyl]- 4-methyl-2-oxo-N-[2-(trifluoromethyl)benzyl]- 1,3-oxazolidine-3- carboxamide 465.10 465.15 8

(4S,5R)-5-[3-fluoro-5- (trifluoromethyl)phenyl]- N-(2- methoxybenzyl)-4-methyl-2-oxo-1,3- oxazolidine-3- carboxamide 427.13 427.22 9

(4S,5R)-N-[3- (dimethylamino)benzyl]- 5-[3-fluoro-5-(trifluoromethyl)phenyl]- 4-methyl-2-oxo-1,3- oxazolidine-3- carboxamide440.16 440.25 10

(4S,5R)-5-[3,5-bis (trifluoromethyl)phenyl]- 4-methyl-2-oxo-N-(quinoxalin-5- ylmethyl)-1,3- oxazolidine-3- carboxamide 499.12 499.0011

(4S,5R)-N-(2,3- dihydro-1,4- benzodioxin-5- ylmethyl)-5-[3-fluoro- 5-(trifluoromethyl)phenyl]- 4-methyl-2-oxo-1,3- oxazolidine-3- carboxamide455.12 454.90 12

(4S,5R)-5-[3-fluoro-5- (trifluoromethyl)phenyl]- N-(1H-indol-7-ylmethyl)-4-methyl-2- oxo-1,3-oxazolidine-3- carboxamide 436.13 436.1613

(4S,5R)-N-(2- ethoxybenzyl)-5-[3- fluoro-5- (trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3- oxazolidine-3- carboxamide 441.14 441.04 14

(4S,5R)-5-[3-fluoro-5- (trifluoromethyl)phenyl]- 4-methyl-2-oxo-N-(thieno[3,2-c]pyridin-4- ylmethyl)-1,3- oxazolidine-3- carboxamide454.08 454.00 15

(4S,5R)-4-methyl-N- (1,6-naphthyridin-8- ylmethyl)-2-oxo-5-[3-(trifluoromethyl)phenyl]- 1,3-oxazolidine-3- carboxamide 431.38 431.5416

(4S,5R)-5-[3-fluoro-5- (trifluoromethyl)phenyl]- 4-methyl-N-(2-methylbenzyl)-2-oxo- 1,3-oxazolidine-3- carboxamide 411.13 411.23 17

(4S,5R)-5-[3,5- bis(trifluoromethyl) phenyl]-N-(furo[2,3-c]pyridin-7-ylmethyl)- 4-methyl-2-oxo-1,3- oxazolidine-3- carboxamide488.10 488.10 18

(4S,5R)-N- (isoquinolin-4- ylmethyl)-4-methyl-2- oxo-5-[3-(trifluoromethyl)phenyl]- 1,3-oxazolidine-3- carboxamide 430.39 430.2719

(4S,5R)-5-[3,5- bis(trifluoromethyl) phenyl]-4-methyl-2-oxo- N-(1,2,3,4-tetrahydronaphthalen- 1-ylmethyl)-1,3- oxazolidine-3- carboxamide 501.16501.10 20

(4S,5R)-5-[3-fluoro-5- (trifluoromethyl)phenyl]- 4-methyl-N-{[4-methyl-2-(1- methylethyl)-1,3- thiazol-5-yl]methyl}-2-oxo-1,3-oxazolidine-3- carboxamide 460.12 460.20 21

(4S,5R)-N-(2- chlorobenzyl)-5-[3- fluoro-5- (trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3- oxazolidine-3- carboxamide 431.07 431.00 22

(4S,5R)-5-[3-fluoro-5- (trifluoromethyl)phenyl]- 4-methyl-2-oxo-N-(quinoxalin-5- ylmethyl)-1,3- oxazolidine-3- carboxamide 449.12 449.1023

(4S,5R)-5-[3-fluoro-5- (trifluoromethyl)phenyl]- 4-methyl-2-oxo-N-(quinolin-4-ylmethyl)- 1,3-oxazolidine-3- carboxamide 448.12 448.10 24

(4S,5R)-N-(2- methoxybenzyl)-4- methyl-2-oxo-5-[3-(trifluoromethyl)phenyl]- 1,3-oxazolidine-3- carboxamide 409.14 409.2525

(4S,5R)-5-(3-bromo-5- fluorophenyl)-N- (isoquinolin-4-ylmethyl)-4-methyl-2- oxo-1,3-oxazolidine-3- carboxamide 458.05; 460.05458.16; 460.16 26

(4S,5R)-5-(3- cyclopropyl-5- fluorophenyl)-N- (isoquinolin-4-ylmethyl)-4-methyl-2- oxo-1,3-oxazolidine-3- carboxamide 420.17 420.1627

(4S,5R)-5-[3-(1,1- difluoroethyl)phenyl]- N-(isoquinolin-4-ylmethyl)-4-methyl-2- oxo-1,3-oxazolidine-3- carboxamide 426.16 426.1228

(4S,5R)-5-[3,5- bis(trifluoromethyl) phenyl]-N-[(3- bromopyridin-2-yl)methyl]-4-methyl-2- oxo-1,3-oxazolidine-3- carboxamide 526.02 525.9429

(4S,5R)-5-[3-fluoro-5- (trifluoromethyl)phenyl]- 4-methyl-2-oxo-N-[(1,3,5-trimethyl-1H- pyrazol-4-yl)methyl]- 1,3-oxazolidine-3-carboxamide 429.15 429.20 30

(4S,5R)-5-[3-fluoro-5- (trifluoromethyl)phenyl]- 4-methyl-2-oxo-N-(quinazolin-8- ylmethyl)-1,3- oxazolidine-3- carboxamide 449.37 449.1031

(4S,5R)-5-[3,5- bis(trifluoromethyl) phenyl]-4-methyl-N-[(3-methylpyridin-2- yl)methyl]-2-oxo-1,3- oxazolidine-3- carboxamide 462.13462.00 32

(4S,5R)-5-[3-fluoro-5- (trifluoromethyl)phenyl]- 4-methyl-2-oxo-N-[2-(1H-pyrrol-1- yl)benzyl]-1,3- oxazolidine-3- carboxamide 462.14 462.1933

(4S,5R)-5-[3- (difluoromethyl)phenyl]- N-(isoquinolin-4-ylmethyl)-4-methyl-2- oxo-1,3-oxazolidine-3- carboxamide 412.15 412.2634

(4S,5R)-5-[3-fluoro-5- (trifluoromethyl)phenyl]- 4-methyl-N-(1,5-naphthyridin-4- ylmethyl)-2-oxo-1,3- oxazolidine-3- carboxamide 449.12449.00 35

(4S,5R)-5-[3,5- bis(trifluoromethyl) phenyl]-N-[(2-fluoro-5-methylpyridin-3- yl)methyl]-4-methyl-2- oxo-1,3-oxazolidine-3-carboxamide 480.12 480.00 36

(4S,5R)-N-{2- [(dimethylamino)methyl] benzyl}-5-[3-fluoro- 5-(trifluoromethyl)phenyl]- 4-methyl-2-oxo-1,3- oxazolidine-3- carboxamide454.18 454.24 37

(4S,5R)-5-[3-fluoro-5- (trifluoromethyl)phenyl]- 4-methyl-2-oxo-N-(quinolin-5-ylmethyl)- 1,3-oxazolidine-3- carboxamide 448.12 448.10 38

(4S,5R)-5-[3,5- bis(trifluoromethyl) phenyl]-N-[(3- methoxypyridin-2-yl)methyl]-4-methyl-2- oxo-1,3-oxazolidine-3- carboxamide 478.36 478.1539

(4S,5R)-5-[3-fluoro-5- (trifluoromethyl)phenyl]- N-(1H-indazol-7-ylmethyl)-4-methyl-2- oxo-1,3-oxazolidine-3- carboxamide 437.36 437.1040

(4S,5R)-5-[3-fluoro-5- trifluoromethyl)phenyl]- 4-methyl-2-oxo-N-[(3-oxo-2,3-dihydro- 1H-isoindol-4- yl)methyl]-1,3- oxazolidine-3-carboxamide 452.12 452.20 41

(4S,5R)-5-[3,5- bis(trifluoromethyl) phenyl]-4-methyl-N-[2-(3-methylpyridin-2- yl)ethyl]-2-oxo-1,3- oxazolidine-3- carboxamide 476.14476.00 42

(4S,5R)-5-[3,5- bis(trifluoromethyl) phenyl]-N-(6,7-dihydro- 5H-cyclopenta[b]pyridin-3- ylmethyl)-4-methyl-2- oxo-1,3-oxazolidine-3-carboxamide 488.14 488.00 43

(4S,5R)-N-[(2,4- dimethyl-1,3-thiazol-5- yl)methyl]-5-[3-fluoro- 5-(trifluoromethyl)phenyl]- 4-methyl-2-oxo-1,3- oxazolidine-3- carboxamide432.09 432.20 44

(4S,5R)-5-[3-fluoro-5- (trifluoromethyl)phenyl]- 4-methyl-N-[2-(methylsulfonyl)benzyl]- 2-oxo-1,3- oxazolidine-3- carboxamide 475.10475.14 45

(4S,5R)-5-[3,5- bis(trifluoromethyl) phenyl]-4-methyl-N-[(2-morpholin-4-ylpyridin- 3-yl)methyl]-2-oxo- 1,3-oxazolidine-3-carboxamide 533.15 533.10 46

(4S,5R)-5-[3-fluoro-5- (trifluoromethyl)phenyl]- N-hydroxy-4-methyl-N-(naphthalen-1- ylmethyl)-2-oxo-1,3- oxazolidine-3- carboxamide 463.39463.00 47

(4S,5R)-5-[3-fluoro-5- (trifluoromethyl)phenyl]- N-(imidazo[2,1-b][1,3]thiazol-5- ylmethyl)-4-methyl-2- oxo-1,3-oxazolidine-3-carboxamide 443.39 443.05 48

(4S,5R)-5-[3-fluoro-5- (trifluoromethyl)phenyl]- N-(isoquinolin-4-ylmethyl)-4-methyl-2- oxo-1,3-oxazolidine-3- carboxamide 448.38 448.1149

(4S,5R)-5-[3,5- bis(trifluoromethyl) phenyl]-N-(2,3-dihydro-1,4-benzodioxin-5- ylmethyl)-4-methyl-2- oxo-1,3-oxazolidine-3-carboxamide 505.12 504.90

Example 50(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-(hydroxymethyl)-N-(isoquinolin-4-ylmethyl)-2-oxooxazolidine-3-carboxamide

Step 1: Benzyl(S)-(3-hydroxy-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate

To a solution of (benzyloxy)carbonyl)-L-serine (170.0 g, 0.8 mol) andHNMe(OMe) HCl (116.0 g, 0.9 mol) in DCM (1.8 L) was stirred at −15° C.for 5 min. Then NMM (220 mL, 0.9 mol) and EDCl (160.0 g, 0.9 mol) wereadded in portions to keep the temperature below −5° C. After addition,the mixture was stirred at −5° C. for 3 h. The reaction was quenchedwith ice-cooled 1 N HCl (800 mL). The organic phase was separated andwashed with 1 N HCl (300 mL×2), saturated NaHCO₃, dried and concentratedto afford the title compound. ¹H NMR (CDCl₃, 400 MHz): δ 7.36-7.31 (m,5H), 5.91 (s, 1H), 5.11 (d, J=2.0 Hz, 2H), 4.87 (s, 1H), 3.85 (s, 2H),3.77 (s, 3H), 3.22 (s, 3H). LC-MS m/z [M+H]⁺ 282.90 (calc'd 283.12).

Step 2: benzyl(S)-(3,8,8,9,9-pentamethyl-4-oxo-2,7-dioxa-3-aza-8-siladecan-5-yl)carbamate

To a solution of benzyl(S)-(3-hydroxy-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (20.0g, 72 mmol) in DCM (400 mL) was added imidazole (12.0 g, 176 mmol) andTBDMSCl (16.0 g, 106 mmol). After stirring at rt for 2 h, the mixturewas quenched with aqueous NH₄Cl, extracted with DCM, washed with water,brine, dried, concentrated and purified by flash chromatography(hexane:EtOAc=15:1) to afford the title compound. ¹H NMR (CDCl₃, 400MHz): δ 7.36-7.29 (m, 5H), 5.63 (s, 1H), 5.14-5.06 (m, 2H), 4.81 (s,1H), 3.90-3.80 (m, 2H), 3.73 (s, 3H), 3.21 (s, 3H), 0.83 (s, 9H), 0.01(s, 6H). LC-MS m/z [M+H]⁺ 396.90 (calc'd 396.21).

Step 3: benzyl(S)-(1-(3,5-bis(trifluoromethyl)phenyl)-3-((tert-butyldimethylsilyl)oxy)-1-oxopropan-2-yl)carbamate

A mixture of benzyl(S)-(3,8,8,9,9-pentamethyl-4-oxo-2,7-dioxa-3-aza-8-siladecan-5-yl)carbamate(23.0 g, 58 mmol), 1-bromo-3,5-bis-trifluoromethylbenzene (27.0 g, 70mmol) in anhydrous THF (200 mL) was stirred at −10° C. for 5 min. TheniPrMgCl (73 mL, 2 M in THF) was added dropwise to keep the temperaturebelow −5° C. After addition, the mixture was stirred at rt overnight.The mixture was quenched by 3 N HCl, extracted with EtOAc, washed withwater. The organic layer was evaporated and purified by flashchromatography (Petroleum ether:EtOAc=10:1) to afford the titlecompound. ¹H NMR (CDCl₃, 400 MHz): δ 8.37 (s, 2H), 8.08 (s, 1H),7.37-7.34 (m, 5H), 5.84 (d, J=4.0 Hz, 1H), 5.39-5.37 (m, 1H), 5.13 (s,2H), 4.02-3.84 (m, 2H), 0.70 (s, 9H), −0.10 (d, J=5.6 Hz, 6H). LC-MS m/z[M+H]⁺ 549.90 (calc'd 550.18).

Step 4: Benzyl((1R,2S)-1-(3,5-bis(trifluoromethyl)phenyl)-3-((tert-butyldimethylsilyl)oxy)-1-hydroxypropan-2-yl)carbamate

A mixture of benzyl(S)-(1-(3,5-bis(trifluoromethyl)phenyl)-3-((tert-butyldimethylsilyl)oxy)-1-oxopropan-2-yl)carbamate(10.0 g, 18 mmol), Al(OiPrO)₃ (3.9 g, 18 mmol), iPrOH (15.6 mL, 198mmol) in anhydrous toluene (200 mL) was stirred at 60° C. overnight.Cooled to rt, the mixture was washed with water, dried and concentrated.It was purified by flash chromatography (Petroleum ether:EtOAc=5:1) toafford the title compound. ¹H NMR (CDCl₃, 400 MHz): δ 7.89-7.79 (m, 3H),7.40-7.31 (m, 5H), 5.60 (s, 1H), 5.15-5.03 (m, 2H), 4.45-4.35 (m, 1H),3.95 (s, 1H), 3.69-3.61 (m, 2H), 0.91 (s, 9H), 0.04 (d, J=5.6 Hz, 6H).LC-MS m/z [M+H]⁺ 551.90 (calc'd 552.19).

Step 5:(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-(((tert-butyldimethylsilyl)oxy)-methyl)oxazolidin-2-one

A mixture of benzyl((1R,2S)-1-(3,5-bis(trifluoromethyl)phenyl)-3-((tert-butyldimethylsilyl)oxy)-1-hydroxypropan-2-yl)carbamate(20.0 g, 36 mmol), KOH (20 mL, 48% aq.) in toluene (200 mL) was stirredat rt overnight. The mixture was diluted with EtOAc, washed with waterand brine, purified by flash chromatography (Petroleum ether:EtOAc=5:1)to afford the title compound. ¹H NMR (CDCl₃, 400 MHz): δ 7.88 (s, 1H),7.84 (s, 2H), 5.86 (s, 1H), 5.77 (s, 1H), 4.17 (t, J=4.2 Hz, 1H),3.29-3.21 (m, 2H), 0.769 (s, 9H), −0.11 (d, J=5.6 Hz, 6H). LC-MS m/z[M+H]⁺ 443.90 (calc'd 444.14).

Step 6:(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxooxazolidine-3-carbonylchloride

N-Butyl lithium (0.39 mL, 2.5 M in hexane, 0.96 mmol) was added slowlyto a stirred mixture of(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)oxazolidin-2-one(200.0 mg, 0.96 mmol) in THF (5 mL) and the mixture was stirred at 0° C.for 20 min. The mixture was cooled to −78° C., and trichloromethylchloroformate (0.23 mL, 0.96 mmol) was added rapidly, and stirredanother 30 min. The mixture was allowed to warm to rt. The solvent andgenerated phosgene was removed by vacuum. The crude product was takendirectly to the next step without further purification.

Step 7:(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-(isoquinolin-4-ylmethyl)-2-oxooxazolidine-3-carboxamide

Isoquinolin-4-ylmethanamine (107.0 mg, 0.68 mmol) was added to a stirredmixture of(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxooxazolidine-3-carbonylchloride (228.0 mg, 0.45 mmol) in DCM (5 mL) and triethylamine (0.23 mL,1.80 mmol) and water (2 drops) and the mixture was stirred from 0° C. tort overnight. The reaction mixture was diluted with DCM (10 mL) andwashed with water (10 mL). Collected organic layer, dried with Na₂SO₄,filtered and concentrated. The crude product was purified by flashchromatography (0% to 50% EtOAc in hexane) to give the title compound.

Step 8:(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-(hydroxymethyl)-N-(isoquinolin-4-ylmethyl)-2-oxooxazolidine-3-carboxamide

Acetyl chloride (0.01 mL, 0.19 mmol) was added to a stirred mixture of(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-(isoquinolin-4-ylmethyl)-2-oxooxazolidine-3-carboxamide(100.0 mg, 0.16 mmol) in MeOH (5 mL) and reaction was stirred at rt for2 h. The reaction mixture was diluted with DCM (10 mL) and washed withwater (10 mL). The organic layers were combined, dried with Na₂SO₄,filtered and concentrated. The crude product was purified by flashchromatography (0% to 50% EtOAc in hexane) to give the title compound.LC-MS m/z [M+H]⁺ 514.04 (calc'd 514.12).

TABLE 2 The compounds in Examples 51-59* were prepared according to theprocedure of Example 50. Calc'd Observed Example Mass Mass NumberStructure Name M + H⁺ M + H⁺ 51

(4S,5R)-4- (hydroxymethyl)-5- [3-methoxy-5- (trifluoromethyl)phenyl]-N-(1,6- naphthyridin-8-yl- methyl)-2-oxo-1,3- oxazolidine-3-carboxamide 477.14 476.71 52

(4S,5R)-5-[3,5- bis(trifluoromethyl) phenyl]-N-(2,3- dimethoxybenzyl)-4-(hydroxymethyl)- 2-oxo-1,3- oxazolidine-3- carboxamide 523.13 523.3053

(4S,5R)-5-[3,5- bis(trifluoromethyl) phenyl]-4- (hydroxymethyl)-N-(1,6-naph- thyridin-8-yl- methyl)-2-oxo-1,3- oxazolidine-3-carboxamide 515.12 515.12 54

(4S,5R)-5-[3,5- bis(trifluoromethyl) phenyl]-4- (hydroxymethyl)-2-oxo-N- (quinazolin-8-yl- methyl)-1,3- oxazolidine-3- carboxamide515.12 515.40 55

(4S,5R)-4- (hydroxymethyl)- N-(isoquinolin-4- ylmethyl)-5-[3- methoxy-5-(trifluoromethyl) phenyl]-2-oxo- 1,3-oxazolidine- 3-carboxamide 476.42476.28 56

(4S,5R)-5-[3,5-bis (trifluoromethyl) phenyl]-4- (hydroxymethyl)-N-(2-methoxy- benzyl)-2-oxo- 1,3-oxazolidine- 3-carboxamide 493.12493.85 57

(4S,5R)-5-[3- fluoro-5- (trifluoromethyl) phenyl]-4- (hydroxymethyl)-N-(isoquinolin-4- ylmethyl)-2-oxo- 1,3-oxazolidine- 3-carboxamide 464.12464.26 58

(4S,5R)-4- (hydroxymethyl)- 5-[3-methoxy-5- (trifluoromethyl)phenyl]-2-oxo-N- (quinoxalin-5- ylmethyl)-1,3- oxazolidine-3-carboxamide 477.13 477.28 59

(4S,5R)-4- (hydroxymethyl)- 5-[3-methoxy-5- (trifluoromethyl)phenyl]-2-oxo-N- (quinazolin-8- ylmethyl)-1,3- oxazolidine-3-carboxamide 477.13 477.15 *The compounds in Examples 50-59 were purifiedusing either flash chromatography or by mass triggered HPLC using thefollowing conditions: column: Waters Sunfire C18, 5u, 19 × 100 mm;solvent: gradient range: 10-15% initial to 70-98% final MeCN (either0.1% formic acid or TFA) in water (0.1% formic acid or TFA) 50 mL/min, 8min run time.

Example 60(4S,5S)—N-((1,6-naphthyridin-8-yl)methyl)-5-(6-methoxy-4-(trifluoromethyl)pyridin-2-yl)-4-methyl-2-oxooxazolidine-3-carboxamide

Step 1: 2,6-dibromo-4-(trifluoromethyl)pyridine

A mixture of 2,6-dichloro-4-(trifluoromethyl)pyridine (5.0 g, 23.2 mmol)and 30% HBr in acetic acid (4 mL) were heated at 100° C. for 24 h in asealed tube. The reaction mixture was cooled to 0° C., neutralized with6 N NaOH and extracted with diethyl ether. The ether layer wasevaporated and crude product was purified by flash chromatography (0% to10% EtOAc in hexane) to provide the title compound.

Step 2: 2-(allyloxy)-6-bromo-4-(trifluoromethyl)pyridine

To a solution of prop-2-en-1-ol (3.6 mL, 52.5 mmol) in THF (40 mL) wasadded NaH (2.1 g, 52.5 mmol) portion wise at 0° C. The resultingsolution was slowly warmed to rt and stirred for 10 min. Then thereaction mixture was cooled to 0° C. and was added a solution of2,6-dibromo-4-(trifluoromethyl)pyridine (16.0 g, 52.5 mmol) in THF (50mL). The resulting mixture was slowly warmed to rt and stirred for 30min. The reaction was diluted with NH₄Cl, then extracted with ethylacetate, and purified by flash chromatography (0% to 10% EtOAc inhexane) to provide the title compound.

Step 3: benzyl(S)-(1-(6-(allyloxy)-4-(trifluoromethyl)pyridin-2-yl)-1-oxopropan-2-yl)carbamate

To a solution of nBuLi (18.0 mL, 45.1 mmol) in THF (25 mL) was added asolution of 2-(allyloxy)-6-bromo-4-(trifluoromethyl)pyridine (12.7 g,45.1 mmol) in THF (20 mL) at −78° C. The resulting solution was stirredat −78° C. for 20 min and then was added a solution of (S)-benzyl(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (6.0 g, 22.5 mmol)in 20 mL THF. The reaction was slowly warmed to 0° C. over 1 h, andquenched with NH₄Cl, extracted with ethyl acetate and purified usingflash chromatography (0% to 100% EtOAc in hexane to provide the titlecompound. LC-MS m/z [M+H]⁺ 409.25 (calc'd 409.13).

Step 4: benzyl((1S,2S)-1-(6-(allyloxy)-4-(trifluoromethyl)pyridin-2-yl)-1-hydroxypropan-2-yl)carbamate

To a solution of (S)-benzyl(1-(6-(allyloxy)-4-(trifluoromethyl)pyridin-2-yl)-1-oxopropan-2-yl)carbamate(5.0 g, 12.2 mmol) in the mixture of toluene (10 mL) and 2-propanol (5mL) was added aluminum isopropoxide (0.5 g, 2.4 mmol), and the resultingsolution was heated at 50° C. for 4 h when the LCMS indicated thecompletion of reaction. The reaction mixture was diluted with brine andextracted with ethyl acetate. The organic layer was dried with MgSO₄,evaporated and purified by flash chromatography (0% to 10% EtOAc inhexane, 80 g Redisep™ column) to provide the title compound. LC-MS m/z[M+H]⁺ 411.26 (calc'd 411.13).

Step 5:(4S,5S)-5-(6-(allyloxy)-4-(trifluoromethyl)pyridin-2-yl)-4-methyloxazolidin-2-one

To a solution of benzyl(1S,2S)-1-(6-(allyloxy)-4-(trifluoromethyl)pyridin-2-yl)-1-hydroxypropan-2-yl)carbamate(900.0 mg, 2.19 mmol) in THF (3 mL) was added potassiumbis(trimethylsilyl)-amide (4.82 mL, 4.82 mmol) at −20° C. The reactionmixture was stirred at −20° C. for 10 min and slowly warmed to 0° C.Saturated ammonium chloride was added, and the resulting mixture wasextracted with ethyl acetate. The reaction mixture was diluted withethyl acetate, washed with saturated NaHCO₃, and then washed with brine.The organic layer was dried with MgSO₄, evaporated and purified by flashchromatography (0% to 10% EtOAc in hexane) to provide the titlecompound. LC-MS m/z [M+H]⁺ 303.15 (calc'd 303.09).

Step 6: tert-butyl(4S,5S)-5-(6-(allyloxy)-4-(trifluoromethyl)pyridin-2-yl)-4-methyl-2-oxooxazolidine-3-carboxylate

The mixture of(4S,5S)-5-(6-(allyloxy)-4-(trifluoromethyl)-pyridin-2-yl)-4-methyloxazolidin-2-one(300.0 mg, 0.99 mmol), BOC-Anhydride (461 μl, 1.98 mmol) and DMAP (24.2mg, 0.20 mmol) were stirred in a sealed tube for 12 h. The reactionmixture was diluted with DCM and directly loaded into column andpurified by flash chromatography (0% to 10% EtOAc in hexane) to providethe title compound. LC-MS m/z [2M+H]⁺805.49 (calc'd 805.28).

Step 7: tert-butyl(4S,5S)-5-(6-hydroxy-4-(trifluoromethyl)pyridin-2-yl)-4-methyl-2-oxooxazolidine-3-carboxylate

To a solution of (4S,5S)-tert-butyl5-(6-(allyloxy)-4-(trifluoromethyl)pyridin-2-yl)-4-methyl-2-oxooxazolidine-3-carboxylate(400.0 mg, 0.99 mmol) in DCM (2 mL) was added Pd(Ph₃)₄(115.0 mg, 0.10mmol) followed by 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (466.0mg, 2.98 mmol). The resulting mixture was cooled to −78° C. and degassedand back filled with nitrogen. This process was repeated three times.Then the reaction mixture was warmed to rt and stirred at rt for 12 h.The reaction mixture was diluted with ethyl acetate, washed withsaturated NaHCO₃. The organic layer was evaporated to dryness andpurified by flash chromatography (0% to 10% EtOAc in hexane) to providethe title compound. LC-MS m/z [2M+H]⁺725.42 (calc'd 725.22).

Step 8: tert-butyl(4S,5S)-5-(6-methoxy-4-(trifluoromethyl)pyridin-2-yl)-4-methyl-2-oxooxazolidine-3-carboxylate

To a solution of (4S,5S)-tert-butyl5-(6-hydroxy-4-(trifluoromethyl)pyridin-2-yl)-4-methyl-2-oxooxazolidine-3-carboxylate(200.0 mg, 0.55 mmol) in DMF (2 mL) was added CsF (252.0 mg, 1.66 mmol)and iodomethane (0.1 mL, 1.66 mmol). The resulting solution was stirredat rt for 12 h. The reaction mixture was quenched with NH₄Cl, thendiluted with ethyl acetate, then washed with brine. The organic layerwas evaporated to dryness, and crude was purified by flashchromatography (0% to 10% EtOAc in hexane) to provide the titlecompound.

Step 9:(4S,5S)-5-(6-methoxy-4-(trifluoromethyl)pyridin-2-yl)-4-methyloxazolidin-2-one

To a solution of (tert-butyl(4S,5S)-5-(6-methoxy-4-(trifluoromethyl)pyridin-2-yl)-4-methyl-2-oxooxazolidine-3-carboxylate(536.0 mg, 1.42 mmol) in DCM (5 mL) was added trifluoroacetic acid (545μL, 7.12 mmol) and the mixture was stirred at rt for 12 h. The reactionwas quenched with saturated NaHCO₃ (5 mL), extracted with DCM, driedover MgSO₄, and concentrated to provide the title compound, which wasused in the next step without further purification.

Step 10:(4S,5S)-5-(6-methoxy-4-(trifluoromethyl)pyridin-2-yl)-4-methyl-2-oxooxazolidine-3-carbonylchloride

n-Butyllithium (0.83 mL, 2.07 mmol) was added to a stirred mixture of(4S,5S)-5-(6-methoxy-4-(trifluoromethyl)pyridin-2-yl)-4-methyloxazolidin-2-one(382.0 mg, 1.38 mmol) in THF at 0° C., and the resulting mixture wasstirred for 30 min. Then, the reaction mixture was cooled to −78° C.,trichloromethyl carbonochloridate (0.25 mL, 2.00 mmol) was addedrapidly, stirred for 30 min at −78° C. The crude was dried on rotavap togive the title compound, which was used in the next step without furtherpurification.

Step 11:(4S,5S)—N-((1,6-naphthyridin-8-yl)methyl)-5-(6-methoxy-4-(trifluoromethyl)pyridin-2-yl)-4-methyl-2-oxooxazolidine-3-carboxamide

(4S,5S)-5-(6-methoxy-4-(trifluoromethyl)-pyridin-2-yl)-4-methyl-2-oxooxazolidine-3-carbonylchloride from step 10 (156.0 mg, 0.46 mmol) was added to a stirredmixture of (1,6-naphthyridin-8-yl)methanamine 3HCl (247.0 mg, 0.92 mmol)and trimethylamine (0.51 mL, 3.69 mmol) in DCM and the mixture wasstirred at rt for 4 h. The reaction mixture was concentrated and theresidue was purified by flash chromatography (0% to 100% EtOAc inhexane) to give the title compound. LC-MS m/z [M+H]⁺ 462.19 (calc'd462.39).

TABLE 3 The compounds in Examples 61-62* were prepared according to theprocedure of Example 60. Calc'd Observed Example Mass Mass NumberStructure Name M + H⁺ M + H⁺ 61

(4S,5S)-N-(isoquinolin- 4-ylmethyl)-4-methyl- 2-oxo-5-[6-(prop-2-en-1-yloxy)-4- (trifluoromethyl) pyridin-2-yl]-1,3- oxazolidine-3-carboxamide 487.44 487.13 62

(4S,5S)-5-[6-ethoxy- 4-(trifluoromethyl) pyridin-2-yl]-4-methyl-2-oxo-N- (quinazolin-8- ylmethyl)-1,3- oxazolidine-3- carboxamide476.42 476.18 *The compounds in Examples 60-62 were purified usingeither silica gel column chromatography or by mass triggered HPLC usingthe following conditions: column: Waters Sunfire C18, 5u, 19 × 100 mm;solvent: gradient range: 10-15% initial to 70-98% final MeCN (either0.1% formic acid or TFA) in water (0.1% formic acid or TFA) 50 mL/min, 8min run time.

Example 63(4S,5S)-4-(hydroxymethyl)-N-(isoquinolin-4-ylmethyl)-5-(6-methoxy-4-(trifluoromethyl)-pyridin-2-yl)-2-oxooxazolidine-3-carboxamide

Example 63 Step 1: 2-bromo-6-methoxy-4-(trifluoromethyl)pyridine

2-bromo-6-methoxy-4-(trifluoromethyl)pyridine was prepared according tothe procedure of Step 2 of Example 60.

Step 2: benzyl(S)-(3-((tert-butyldimethylsilyl)oxy)-1-(6-methoxy-4-(trifluoromethyl)pyridin-2-yl)-1-oxopropan-2-yl)carbamate

To a solution of nBuLi (3.47 ml, 5.55 mmol) in THF (8 mL) was added asolution of 2-bromo-6-methoxy-4-(trifluoromethyl)pyridine (1.42 g, 5.55mmol) in 3 mL THF at −78° C. The resulting mixture was stirred at −78°C. for 20 min, then was added a solution of (S)-benzyl(3,8,8,9,9-pentamethyl-4-oxo-2,7-dioxa-3-aza-8-siladecan-5-yl)carbamate(1.00 g, 2.52 mmol) in 4 mL THF. The reaction mixture was slowly warmedto 0° C. over 1 h. The reaction was quenched with NH₄Cl, and brine,extracted with ethyl acetate, evaporated, and purified by flashchromatography (0% to 100% EtOAc in hexane) to provide the titlecompound.

Steps 3-7:(4S,5S)-4-(hydroxymethyl)-N-(isoquinolin-4-ylmethyl)-5-(6-methoxy-4-(trifluoro-methyl)-pyridin-2-yl)-2-oxooxazolidine-3-carboxamide

Benzyl(S)-(3-((tert-butyldimethyl-silyl)oxy)-1-(6-methoxy-4-(trifluoromethyl)pyridin-2-yl)-1-oxopropan-2-yl)carbamate(the product of Step 2 of Example 63) was converted to the titlecompound following the procedure of Steps 4-8 of Example 50. LC-MS m/z[M+H]⁺ 477.17 (calc'd 477.14).

TABLE 4 Example 64 was prepared according to the procedure of Example63. Calc'd Observed Example Mass Mass Number Structure Name M + H⁺ M +H⁺ 64

(4S,5S)-4- (hydroxymethyl)-5- [6-methoxy-4- (trifluoromethyl)pyridin-2-yl]-N- (1,6-naphthyridin- 8-ylmethyl)-2-oxo-1,3-oxazolidine-3- carboxamide 478.39 478.30

Example 65(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-(3-(isoquinolin-4-yl)propanoyl)-4-methyloxazolidin-2-one

(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-(3-(isoquinolin-4-yl)propanoyl)-4-methyloxazolidin-2-one

1,1′-Carbonyldiimidazoele (0.79 g, 4.87 mmol) was added to a stirredmixture of 3-(isoquinolin-4-yl)propanoic acid (0.70 g, 3.48 mmol) inAcCN (60 mL) and the mixture was stirred at rt for 1 h. Then(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one(1.09 g, 3.48 mmol, synthesized according to Steps 1-2 in of Example 1)was added, followed by the addition of DBU (1.56 mL, 4.87 mmol). Theresulting mixture was stirred at rt for 12 h. Then the reaction mixturewas concentrated and purified by flash chromatography (0% to 60% EtOAcin hexane) to provide the title compound. LC-MS m/z [M+H]⁺ 497.22(calc'd 497.40).

TABLE 5 The compounds in Examples 66-89* were prepared according to theprocedure of Example 65. Calc'd Observed Example Mass Mass NumberStructure Name M + H⁺ M + H⁺ 66

(4S,5R)-5-[3-chloro-5- (trifluoromethyl)phenyl]-4-methyl-3-(3-naphthalen- 1-ylpropanoyl)-1,3- oxazolidin-2-one 462.11462.23 67

(4S,5R)-5-[3,5- bis(trifluoromethyl) phenyl]-4-methyl-3-(3-naphthalen-1- ylpropanoyl)-1,3- oxazolidin-2-one 496.13 495.99 68

(4S,5R)-3-[3-(1- benzothiophen-4- yl)propanoyl]-5-[3,5-bis(trifluoromethyl) phenyl]-4-methyl-1,3- oxazolidin-2-one 502.09501.93 69

(4S,5R)-4-methyl-3-(3- naphthalen-1- ylpropanoyl)-5-[3-(trifluoromethoxy) phenyl]-1,3-oxazolidin- 2-one 444.14 444.34 70

(4S,5R)-5-[3-fluoro-5- (trifluoromethyl)phenyl]- 3-(3-isoquinolin-4-ylpropanoyl)-4-methyl- 1,3-oxazolidin-2-one 447.39 447.02 71

(4S,5R)-5-[3,5- bis(trifluoromethyl) phenyl]-4-methyl-3- (naphthalen-1-ylacetyl)-1,3- oxazolidin-2-one 482.12 482.28 72

(4S,5R)-3-(3-isoquinolin- 4-ylpropanoyl)-4-methyl- 5-[3-(trifluoromethoxy) phenyl]-1,3-oxazolidin- 2-one 445.14 444.90 73

(4S,5R)-5-[3,5- bis(trifluoromethyl) phenyl]-4-methyl-3- (3-quinolin-5-ylpropanoyl)-1,3- oxazolidin-2-one 497.13 497.16 74

(4S,5R)-3-(3-isoquinolin- 5-ylpropanoyl)-4-methyl- 5-[3-methyl-5-(trifluoromethyl)phenyl]- 1,3-oxazolidin-2-one 443.43 443.27 75

(4S,5R)-5-[3,5- bis(trifluoromethyl) phenyl]-3-(3- isoquinolin-8-ylpropanoyl)-4-methyl- 1,3-oxazolidin-2-one 497.13 497.40 76

5-[3,5- bis(trifluoromethyl) phenyl]-3-(3- isoquinolin-4-ylpropanoyl)-1,3- oxazolidin-2-one 483.38 483.26 77

(4S,5R)-5-(3,5- dimethylphenyl)-3-(3- isoquinolin-4-ylpropanoyl)-4-methyl- 1,3-oxazolidin-2-one 389.46 389.19 78

(4S,5R)-3-(3-isoquinolin- 4-ylpropanoyl)-4-methyl-5-(3,4,5-trifluorophenyl)- 1,3-oxazolidin-2-one 415.38 415.32 79

(4S,5R)-5-(3-fluoro-5- methylphenyl)-3-(3- isoquinolin-4-ylpropanoyl)-4-methyl- 1,3-oxazolidin-2-one 393.42 393.01 80

(4S,5R)-5-(3- fluorophenyl)-3-(3- isoquinolin-4- ylpropanoyl)-4-methyl-1,3-oxazolidin-2-one 379.40 379.18 81

(4S,5S)-5-(6- methoxypyridin-2-yl)-4- methyl-3-(3-naphthalen-1-ylpropanoyl)-1,3- oxazolidin-2-one 391.17 391.34 82

(4S,5R)-5-(3,4- difluorophenyl)-3-(3- isoquinolin-4-ylpropanoyl)-4-methyl- 1,3-oxazolidin-2-one 397.39 397.20 83

(4S,5R)-5-[3,5- bis(trifluoromethyl) phenyl]-4-ethyl-3- (3-isoquinolin-4-ylpropanoyl)-1,3- oxazolidin-2-one 511.43 511.18 84

(4S,5S)-5-(6- bromopyridin-2-yl)-4- methyl-3-(3-naphthalen-1-ylpropanoyl)-1,3- oxazolidin-2-one 439.97; 441.07 438.80; 441.08 85

(5S)-5-[3,5- bis(trifluoromethyl) phenyl]-3-(3- isoquinolin-4-ylpropanoyl)-1,3- oxazolidin-2-one 483.11 483.17 86

5-(2,3-difluorophenyl)-3- (3-isoquinolin-4- ylpropanoyl)-1,3-oxazolidin-2-one 383.36 383.24 87

(4S,5R)-3-(3- isoquinolin-4- ylpropanoyl)-5-(3- methoxyphenyl)-4-methyl-1,3- oxazolidin-2-one 391.17 391.43 88

(4S,5R)-5-[3-bromo-5- (trifluoromethyl)phenyl]- 3-(3-isoquinolin-4-ylpropanoyl)-4-methyl- 1,3-oxazolidin-2-one 507.05; 509.05 507.61;508.90 89

(4S,5S)-3-(3-(isoquinolin- 4-yl)propanoyl)-4-methyl-5-(4-(trifluoromethyl) pyridin-2-yl)oxazolidin- 2-one 430.14 430.16 *Thecompounds in Examples 65-89 were purified by either silica gel columnchromatography or by mass triggered HPLC using the following conditions:column: Waters Sunfire C18, 5u, 19 × 100 mm; solvent: gradient range:10-15% initial to 70-98% final MeCN (either 0.1% formic acid or TFA) inwater (0.1% formic acid or TFA) 50 mL/min 8 min run time.

Example 90(4S,5R)-3-(2-(2,3-dimethylphenoxy)acetyl)-4-methyl-5-(3-(trifluoromethyl)-phenyl)oxazolidin-2-one

Step 1:(4S,5R)-3-(2-bromoacetyl)-4-methyl-5-(3-(trifluoromethyl)phenyl)oxazolidin-2-one

To a stirred solution of(4S,5R)-4-methyl-5-(3-(trifluoromethyl)phenyl)oxazolidin-2-one (1.0 g,4.08 mmol) in THF (20 mL) was added n-butyllithium in hexane (1.79 mL,4.49 mmol) dropwise at 0° C. under Ar atmosphere. After stirring for 15min, 2-bromoacetyl bromide (0.46 mL, 5.30 mmol) was added dropwise, andthe mixture was stirred at the same temperature for 3 h. The resultingmixture was quenched with saturated aqueous NaHCO₃ and extracted withethyl acetate. The combined organic layers were dried over Na₂SO₄ andevaporated. The residue was purified by flash chromatography (0% to 30%EtOAc in hexane) to give the title compound.

Step 2:(4S,5R)-3-(2-(2,3-dimethylphenoxy)acetyl)-4-methyl-5-(3-(trifluoromethyl)phenyl)-oxazolidin-2-one

To a solution of(4S,5S)-3-(2-bromoacetyl)-4-methyl-5-(3-(trifluoro-methyl)phenyl)oxazolidin-2-one(50.0 mg, 0.14 mmol) in DMF (1 mL) was added DIPEA (36 μL, 0.20 mmol)and 2,3 dimethylphenol (16.0 mg, 0.14 mmol). The resulting mixture washeated at 60° C. for 12 h. The reaction mixture was allowed to cool tort and added directly onto Gilson reverse phase, eluting with 40% to100% MeCN/H₂O/0.1% TFA to yield the title compound. LC-MS m/z [M+H]⁺408.11 (calc'd 408.14).

TABLE 6 Example 91 was prepared according to the procedure of Example90. Ex- am- Ob- ple Calc'd served Num- Mass Mass ber Structure Name M +H⁺ M + H⁺ 91

(4S,5R)-5- [3,5- bis(trifluoro- methyl) phenyl]-4- methyl-3-[(naphthalen- 1-yloxy) acetyl]-1,3- oxazolidin- 2-one 498.11 498.98

Example 92(4S,5R)-5-(3-fluoro-5-(trifluoromethyl)phenyl)-4-methyl-3-(3-(6-methyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)propanoyl)oxazolidin-2-one

Step 1:(4S,5R)-3-acryloyl-5-(3-fluoro-5-(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one

To a solution of(4S,5R)-5-(3-fluoro-5-(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one(0.5 g, 1.90 mmol, synthesized according to the procedure of steps 1-2of Example 1) in THF (10 mL) was added lithium chloride (0.10 g, 2.38mmol) followed by triethylamine (0.33 mL, 2.375 mmol) at 0° C. Asolution of acrylic anhydride (0.30 g, 2.38 mmol) in 1 mL THF was addedinto the above mixture. The mixture was slowly warmed to rt and stirredat rt for 2 h. LCMS indicated that the reaction was completed. Thereaction mixture was concentrated to dryness and added 10 mL 1 N HCl.The resulting solution was extracted with DCM (20 mL), then the DCMlayer was washed with 1:1 water and saturated NaHCO₃ (10 mL). The DCMlayer was evaporated and purified by flash chromatography (0% to 15%EtOAc in hexane) to yield the title compound.

Step 2:(4S,5R)-5-(3-fluoro-5-(trifluoromethyl)phenyl)-4-methyl-3-(3-(6-methyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)propanoyl)oxazolidin-2-one

(4S,5R)-3-acryloyl-5-(3-fluoro-5-(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one(63.0 mg, 0.14 mmol) was dissolved in DMSO (2 mL) in a microwave tubeand 6-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (450.0 mg, 3.00mmol) was added. The reaction vessel was capped, purged with nitrogenand stirred at 50° C. overnight. The mixture was loaded directly onto asilica gel column for flash chromatography (0% to 40% EtOAc in hexane).The crude product was further purified on Gilson reverse phase HPLC (20%to 100% MeCN/H₂O/TFA 0.1%) to afford the title compound. LC-MS m/z[M+H]⁺ 468.64 (calc'd 468.15).

Example 93(5R,6S)-6-(3,5-bis(trifluoromethyl)phenyl)-N-(isoquinolin-4-ylmethyl)-5-methyl-2-oxo-1,3-oxazinane-3-carboxamide

Example 93 Step 1: benzyl(3-(methoxy(methyl)amino)-2-methyl-3-oxopropyl)carbamate

The title compound was prepared according to the procedure of Step 1 ofExample 50.

Step 2: benzyl(3-(3,5-bis(trifluoromethyl)phenyl)-2-methyl-3-oxopropyl)carbamate

The title compound was prepared according to the procedure of Step 1 ofExample 1.

Step 3: benzyl(3-(3,5-bis(trifluoromethyl)phenyl)-3-hydroxy-2-methylpropyl)carbamate

To a solution of benzyl(3-(3,5-bis(trifluoromethyl)phenyl)-2-methyl-3-oxopropyl)carbamate(622.0 mg, 1.44 mmol) in ethanol (15 mL) was added lithiumtri-tert-butoxyaluminum hydride (1.0 M in THF, 7.18 mL, 7.18 mmol) at−78° C. The resulting solution was stirred for 1 h, then quenched with 1M HCl (25 mL), diluted with water, and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried with MgSO₄,filtered, and the solvent was evaporated under reduced pressure. Theresulting residue was taken directly to the next step without furtherpurification.

Step 4: 6-(3,5-bis(trifluoromethyl)phenyl)-5-methyl-1,3-oxazinan-2-one

To a solution of benzyl(3-(3,5-bis(trifluoromethyl)phenyl)-3-hydroxy-2-methylpropyl)carbamate(625.0 mg, 1.44 mmol) in THF (5 mL) was added NaH (68.9 mg, 1.72 mmol)at −25° C. The resulting mixture was slowly warmed to rt over 12 h, andthen heated at 38° C. for 12 h. Then the reaction mixture was cooled tort, and quenched with 1 N HCl, and extracted with ethyl acetate. Thecombined organic fractions were washed with brine, dried with MgSO₄,filtered, and the solvent was evaporated under reduced pressure. Theresulting residue was purified by flash chromatography (0% to 75% EtOAcin hexane) to provide the title compound as a mixture of 7:3 (cis:trans)diastereomers. LC-MS m/z [M+H]⁺ 328.39 (calc'd 328.07).

Step 5:6-(3,5-bis(trifluoromethyl)phenyl)-5-methyl-2-oxo-1,3-oxazinane-3-carbonylchloride

The title compound was prepared according to the procedure of Step 6 ofExample 50.

Step 6:6-(3,5-bis(trifluoromethyl)phenyl)-N-(isoquinolin-4-)-5-methyl-2-oxo1,3-oxazinane-3-carboxamide

6-(3,5-bis(trifluoromethyl)phenyl)-5-methyl-2-oxo-1,3-oxazinane-3-carbonylchloride (119.0 mg, 0.30 mmol) was added to a stirred mixture ofisoquinolin-4-ylmethanamine (97.0 mg, 0.61 mmol) in dichloromethane andwater (2 drops) at 0° C. The resulting mixture was slowly warmed to rtover 12 h and concentrated in vacuo. The resulting residue was separatedinto cis and trans diastereomers using flash chromatography on silicagel (0% to 100% EtOAc in hexane). The racemic cis diastereomer wasfurther submitted for SFC separation (method: isocratic, 25% of EtOH inCO₂; back pressure 120 bar, 40° C.; flow rate: 3 ml/min; column: OJ-H,4.6×250 mm, 5 μm) to afford the (5R,6S) enantiomer (R_(t)=2.49 min) andthe (5S,6R) enantiomer (R_(t)=2.18 min). The two enantiomers of thetrans product were obtained using the same conditions.

TABLE 7 Example 94 was prepared according to the procedure of Example93. Calc'd Observed Example Mass Mass Number Structure Name M + H⁺ M +H⁺ 94

(5R,6S)-6-[3-methoxy-5- (trifluoromethyl)phenyl]- 5-methyl-N-(1,6-naphthyridin-8-ylmethyl)- 2-oxo-1,3-oxazinane-3- carboxamide 475.15475.29

Example 95(5R,6S)-6-(3,5-bis(trifluoromethyl)phenyl)-N-(isoquinolin-4-ylmethyl)-5-methyl-2-oxo-1,3-oxazinane-3-carboxamide

Step 1: benzyl((1R,2S)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-hydroxypropan-2-yl)carbamate

To a solution of (S)-benzyl(1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-oxopropan-2-yl)carbamate (3.36g, 9.10 mmol) in the mixture of toluene (9 mL) and 2-propanol (6 mL) wasadded aluminum isopropoxide (0.37 g, 1.82 mmol). The reaction mixturewas heated at 50° C. for 6 h, then diluted with water, and extractedwith EtOAc twice. The combined organic layers were dried over Na₂SO₄,and concentrated to give the title compound. LC-MS m/z [M+H]⁺ 372.26(calc'd 372.11).

Step 2:(1R,2S)-2-amino-1-(3-fluoro-5-(trifluoromethyl)phenyl)propan-1-ol

To a solution of benzyl((1R,2S)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-hydroxypropan-2-yl)carbamate(3.35 g, 9.02 mmol) in MeOH (80 mL) was added 10% Pd/C (0.77 g, 0.72mmol). The resulting mixture was subjected to hydrogenation at rt via H₂balloon for 3 h. Then the mixture was filtered through Celite™ under aN₂ atmosphere, and the filtrate was concentrated to give the titlecompound. LC-MS m/z [M+H]⁺ 238.16 (calc'd 238.11).

Step 3:(1R,2S)-2-(allylamino)-1-(3-fluoro-5-(trifluoromethyl)phenyl)propan-1-ol

To a solution of(1R,2S)-2-amino-1-(3-fluoro-5-(trifluoromethyl)phenyl)propan-1-ol (2.13g, 8.98 mmol) and DBU (1.35 mL, 8.98 mmol) was added dropwise allylbromide (0.78 mL, 8.98 mmol). The resulting solution was stirred at rtover the weekend, then concentrated. The resulting residue was purifiedby flash chromatography (0% to 15% MeOH in DCM) to give the titlecompound. LC-MS m/z [M+H]⁺ 278.17 (calc'd 278.11).

Step 4:N-allyl-N-((1R,2S)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-hydroxypropan-2-yl)nitrousamide

To the mixture of(1R,2S)-2-(allylamino)-1-(3-fluoro-5-(trifluoromethyl)phenyl)propan-1-ol(1.68 g, 6.06 mmol) in THF (30 mL) was added HCl (3.32 mL, 2.74 M, 9.09mmol). The mixture was cooled to 0° C., and sodium nitrite (0.54 g, 7.88mmol) was added. The resulting mixture was allowed to warm from 0° C. tort overnight. Then the mixture was basified by the addition of saturatedNaHCO₃, and extracted with EtOAc three times. The combined organiclayers were washed with brine twice, dried over Na₂SO₄, and concentratedto give the title compound. LC-MS m/z [M+H+MeCN]⁺ 348.25 (calc'd348.13).

Step 5:(1R,2S)-2-(1-allylhydrazinyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)propan-1-ol

To THF (20 mL) was added LiAlH₄ (2M in THF, 6.14 mL, 12.28 mmol) atreflux. Then a solution ofN-allyl-N-((1R,2S)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-hydroxypropan-2-yl)nitrousamide (1.88 g, 6.14 mmol) in THF (20 mL) was added dropwise whilekeeping the solution at reflux for 10 min. The reaction was heated atreflux for 2 h, then cooled to rt and quenched by the dropwise additionof 6 N NaOH. Then saturated sodium potassium tartrate solution (100 mL)was added. The resulting mixture was stirred at rt for 2 h, and thenextracted with EtOAc three times. The combined organic layers were driedover Na₂SO₄, and concentrated to give the title compound. LC-MS m/z[M+H]⁺ 293.21 (calc'd 293.12).

Step 6:(5S,6R)-4-allyl-6-(3-fluoro-5-(trifluoromethyl)phenyl)-5-methyl-1,3,4-oxadiazinan-2-one

A solution of diethyl carbonate (728.0 mg, 6.16 mmol) and(1R,2S)-2-(1-allylhydrazinyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)propan-1-ol(1.80 g, 6.16 mmol) in hexane (100 mL) was heated at reflux. To therefluxing solution was added NaH (246.0 mg, 6.16 mmol) and the resultingreaction mixture was heated at reflux for 4 h. After cooling to rt, themixture was concentrated and the resulting residue was dissolved inEtOAc, then washed with 1 N HCl, saturated NaHCO₃, and brine, then driedover Na₂SO₄ and concentrated. The resulting residue was purified byflash chromatography (silica gel column), 0% to 100% EtOAc in hexane) togive the title compound. LC-MS m/z [M+H]⁺ 319.23 (calc'd 319.11).

Step 7:(5S,6R)-4-allyl-6-(3-fluoro-5-(trifluoromethyl)phenyl)-5-methyl-2-oxo-1,3,4-oxadiazinane-3-carbonylchloride

To the solution of(5S,6R)-4-allyl-6-(3-fluoro-5-(trifluoromethyl)phenyl)-5-methyl-1,3,4-oxadiazinan-2-one(16.0 mg, 0.05 mmol) in THF (4 mL) at −78° C. was added n-butyllithium(35 μL, 0.06 mmol). The resulting solution was stirred at −78° C. for 5min before the addition of diphosgene (7 μL, 0.06 mmol). The reactionwas stirred at −78° C. for 30 min, then warmed to rt and concentrated togive the title compound. LC-MS m/z [M+H−Cl+MeOH]⁺ 377.25 (calc'd377.10).

Step 8:(5S,6R)-4-allyl-6-(3-fluoro-5-(trifluoromethyl)phenyl)-N-(isoquinolin-4-ylmethyl)-5-methyl-2-oxo-1,3,4-oxadiazinane-3-carboxamide

To a solution of(5S,6R)-4-allyl-6-(3-fluoro-5-(trifluoromethyl)phenyl)-5-methyl-2-oxo-1,3,4-oxadiazinane-3-carbonylchloride (19.0 mg, 0.05 mmol) in DCM (3 mL) was addedisoquinolin-4-ylmethanamine dihydrochloride (11.6 mg, 0.05 mmol) and TEA(0.042 mL, 0.30 mmol). The resulting mixture was stirred at rt for 10min, and then concentrated in vacuo. The resulting residue was purifiedby reverse phase HPLC (MeCN in 0.05% TFA)/water (0.05% TFA)) to give thetitle compound. LC-MS m/z [M+H]±503.34 (calc'd 503.16).

Step 9:(5R,6S)-6-(3,5-bis(trifluoromethyl)phenyl)-N-(isoquinolin-4-ylmethyl)-5-methyl-2-oxo-1,3-oxazinane-3-carboxamide

The solution of(5S,6R)-4-allyl-6-(3-fluoro-5-(trifluoromethyl)-phenyl)-N-(isoquinolin-4-ylmethyl)-5-methyl-2-oxo-1,3,4-oxadiazinane-3-carboxamide(230.0 mg, 0.46 mmol), and 1,3-dimethylbarbituric acid (214.0 mg, 1.37mmol) in DCM (10 mL) was bubbled with N₂ for 15 min. Thentetrakis(triphenylphosphine)palladium(0) (26.4 mg, 0.02 mmol) was added.The resulting mixture was heated at 35° C. for three days, thenpartitioned between saturated NaHCO₃ and DCM. The aqueous layer wasseparated and extracted with DCM (3×). The combined organic layers weredried over Na₂SO₄, and concentrated in vacuo. The resulting residue waspurified by flash chromatography (0% to 100% EtOAc in hexane) to give aresidue, which was further purified by reverse phase HPLC (MeCN (0.05%TFA)/water(0.05% TFA)) to give the title compound. LC-MS m/z [M+H]⁺463.29 (calc'd 463.13).

Example 96(4S,5R)—N-(isoquinolin-4-ylmethyl)-5-(4-methoxy-6-(trifluoromethyl)pyrimidin-2-yl)-4-methyl-2-oxooxazolidine-3-carboxamide

Step 1: (4S,5R)-3-(4-methoxybenzyl)-4-methyl-5-vinyloxazolidin-2-one

To a solution of (4S,5R)-4-methyl-5-vinyloxazolidin-2-one (4.08 g, 32.1mmol) in DMF (60 mL) at 0° C. was added NaH (1.54 g, 38.5 mmol). Theresulting mixture was stirred at 0° C. for 30 min, then DMF (15 mL) wasadded, followed by the addition of 4-methoxybenzyl chloride (4.6 mL,33.7 mmol). The resulting mixture was heated at 90° C. for 2 h. Theresulting solid was filtered off and the filtrate was quenched withwater, and concentrated. The resulting residue was dissolved in EtOAc(300 mL) and washed with water (3×), then dried over Na₂SO₄, andconcentrated. The resulting residue was purified by flash chromatography(0% to 100% EtOAc in hexane) to give the title compound. LC-MS m/z[M+H]⁺ 248.11 (calc'd 248.12).

Step 2:(4S,5S)-3-(4-methoxybenzyl)-4-methyl-2-oxooxazolidine-5-carbaldehyde

To a solution of(4S,5R)-3-(4-methoxybenzyl)-4-methyl-5-vinyloxazolidin-2-one (7.54 g,30.5 mmol) in dioxane (200 mL) and water (100 ml) was added sodiumperiodate (26.10 g, 122.0 mmol) and osmium tetroxide (2.5% intert-butanol, 12.40 g, 1.2 mmol). The resulting mixture was stirred atrt over the weekend. After filtration, the filtrate was concentrated andthe resulting residue was partitioned between water and DCM. The aqueousphase was separated and extracted with 30% IPA/DCM three times. Thecombined organic layers were dried over Na₂SO₄, and concentrated to givethe title compound. LC-MS m/z [M+H+MeOH]⁺ 282.14 (calc'd 282.13).

Step 3:(4S,5S)-3-(4-methoxybenzyl)-4-methyl-2-oxooxazolidine-5-carboxylic acid

To a solution of(4S,5S)-3-(4-methoxybenzyl)-4-methyl-2-oxooxazolidine-5-carbaldehyde(7.60 g, 30.5 mmol) in tert-Butanol (40 mL) was added potassiumdihydrogen phosphate (4.98 g, 36.6 mmol) in water (40 mL), followed by2-methyl-2-butene (32.3 mL, 305.0 mmol), and sodium chlorite (5.52 g,61.0 mmol). The reaction mixture was stirred from 0° C. to rt overnight,then acidified to pH 2 by 1 N HCl. The resulting mixture was extractedwith EtOAc, followed by extraction with 30% IPA/DCM (3×150 mL). Thecombined organic layers were dried over Na₂SO₄, and concentrated to givethe crude product, which was partitioned between DCM and 0.5 N NaOH (120mL). The alkaline layer was extracted with DCM (3×), then acidified topH 3 by adding 4 N HCl at 0° C. The resulting precipitate was extractedwith DCM (3×). The combined DCM layers were dried over Na₂SO₄, andconcentrated to give the title compound. LC-MS m/z [M+H]⁺ 266.11 (calc'd266.10).

Step 4: (4S,5S)-2,5-dioxopyrrolidin-1-yl3-(4-methoxybenzyl)-4-methyl-2-oxooxazolidine-5-carboxylate

To a solution of(4S,5S)-3-(4-methoxybenzyl)-4-methyl-2-oxooxazolidine-5-carboxylic acid(7.17 g, 27.0 mmol), and 1-hydroxypyrrolidine-2,5-dione (3.78 g, 28.4mmol) in DCM (100 mL) at 0° C. was added EDC (6.22 g, 32.4 mmol). Thereaction was stirred from 0° C. to rt overnight, then washed with waterthree times, dried over Na₂SO₄, concentrated to give the title compound.LC-MS m/z [M+H]⁺ 363.18 (calc'd 363.11).

Step 5:(4S,5S)-3-(4-methoxybenzyl)-4-methyl-2-oxooxazolidine-5-carboxamide

To a solution of (4S,5S)-2,5-dioxopyrrolidin-1-yl3-(4-methoxybenzyl)-4-methyl-2-oxooxazolidine-5-carboxylate (9.61 g,26.5 mmol) in a mixture of dioxane (120 mL)/DCM (50 mL)/THF (100mL)/water (50 mL) at 0° C. was added dropwise ammonium hydroxide (18.44mL, 133.0 mmol). The reaction mixture was stirred at 0° C. for 10 min,then concentrated. The resulting residue was partitioned between DCM andsaturated NaHCO₃. The aqueous phase was separated and extracted with DCM(3×). The combined organic layers were dried over Na₂SO₄, andconcentrated to give the title compound. LC-MS m/z [M+H]⁺ 265.12 (calc'd265.11).

Step 6:(4S,5S)-3-(4-methoxybenzyl)-4-methyl-2-oxooxazolidine-5-carbonitrile

To the solution of(4S,5S)-3-(4-methoxybenzyl)-4-methyl-2-oxooxazolidine-5-carboxamide(5.77 g, 21.83 mmol) in DMF (40 mL) at 0° C. was added cyanuric chloride(4.83 g, 26.2 mmol). The reaction was stirred from 0° C. for 1 h, thenquenched by the addition of saturated NaHCO₃. The mixture was thenpartitioned between EtOAc (300 mL) and saturated NaHCO₃ (20 mL). Thewater layer was extracted once with EtOAc, and the combined organiclayers were washed with saturated NaHCO₃ (3×), dried over Na₂SO₄, andconcentrated. The resulting residue was purified by flash chromatography(0% to 100% EtOAc in hexane) to give the title compound. LC-MS m/z[M+H]⁺ 247.16 (calc'd 247.10).

Step 7:(4S,5S)-3-(4-methoxybenzyl)-4-methyl-2-oxooxazolidine-5-carboximidamidehydrochloride

To a solution of(4S,5S)-3-(4-methoxybenzyl)-4-methyl-2-oxooxazolidine-5-carbonitrile(0.60 g, 2.4 mmol) and MeOH (0.12 mL, 2.9 mmol) in diethyl ether (20 mL)at 0° C. was bubbled HCl gas and the reaction was stirred for 2 h. Thenthe reaction mixture was concentrated. The resulting residue wasdissolved in MeOH (20 mL) and added to ammonia (7 N in MeOH, 20 mL,140.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h.Then additional ammonia (7 N in MeOH, 40 mL) was added and the resultingreaction mixture was stirred at rt over the weekend, then concentratedto give the title compound. LC-MS m/z [M+H]⁺ 264.14 (calc'd 264.13).

Step 8:(4S,5R)-5-(4-hydroxy-6-(trifluoromethyl)pyrimidin-2-yl)-3-(4-methoxybenzyl)-4-methyloxazolidin-2-one

The mixture of methyl 4,4,4-trifluoro-3-oxobutanoate (240.0 mg, 1.41mmol), DIEA (0.45 mL, 2.57 mmol) and(4S,5S)-3-(4-methoxybenzyl)-4-methyl-2-oxooxazolidine-5-carboximidamidehydrochloride (385.0 mg, 1.28 mmol) in dioxane (12 mL) was heated at120° C. overnight, then concentrated. The resulting residue waspartitioned between DCM and saturated NH₄Cl, and the water layer wasextracted with DCM (2×). The combined organic layers dried over Na₂SO₄,and concentrated. The resulting residue purified on silica gel columnusing EtOAc in hexane (0% to 100%) as eluting solvents to give the titlecompound. LC-MS m/z [M+H]⁺ 384.14 (calc'd 384.11).

Step 9:(4S,5R)-5-(4-hydroxy-6-(trifluoromethyl)pyrimidin-2-yl)-3-(4-methoxybenzyl)-4-methyloxazolidin-2-oneand(4S,5R)-3-(4-methoxybenzyl)-4-methyl-5-(1-methyl-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl)oxazolidin-2-one

To a solution of(4S,5R)-5-(4-hydroxy-6-(trifluoromethyl)pyrimidin-2-yl)-3-(4-methoxybenzyl)-4-methyloxazolidin-2-one(230.0 mg, 0.60 mmol) in DMF (6 mL) was added CsF (273.0 mg, 1.80 mmol)and Mel (0.11 mL, 1.80 mmol). The reaction mixture was stirred at rt for4 h. Then the reaction mixture was partitioned between brine and EtOAc.The organic layer was separated and washed with brine (3×), then driedover Na₂SO₄, and concentrated. The resulting residue was purified onsilica gel column using EtOAc/hexane (0% to 50%) as eluting solvents togive(4S,5R)-5-(4-methoxy-6-(trifluoromethyl)pyrimidin-2-yl)-3-(4-methoxybenzyl)-4-methyloxazolidin-2-one(LC-MS m/z [M+H]⁺ 398.22 (calc'd 398.12), and(4S,5R)-3-(4-methoxybenzyl)-4-methyl-5-(1-methyl-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-2-yl)oxazolidin-2-one(LC-MS m/z [M+H]⁺ 398.21 (calc'd 398.12).

Step 10:(4S,5R)-5-(4-methoxy-6-(trifluoromethyl)pyrimidin-2-yl)-4-methyloxazolidin-2-one

A solution of(4S,5R)-5-(4-methoxy-6-(trifluoromethyl)pyrimidin-2-yl)-3-(4-methoxybenzyl)-4-methyloxazolidin-2-one(65.0 mg, 0.16 mmol) in TFA (4 mL, 51.9 mmol) was heated at 60° C. overthe weekend. The reaction mixture was concentrated, and the resultingresidue was purified on silica gel column using EtOAc/hexane (0% to100%) as eluting solvents to give the title compound. LC-MS m/z [M+H]⁺278.10 (calc'd 278.07).

Step 11: (4S,5R)—N-(isoquinolin-4-ylmethyl)-5-(4-methoxy-6-(tfluoromethyl)pyrimidin-2-yl)-4-methyl-2-oxooxazolidine-3-carboxamide

To a solution of(4S,5R)-5-(4-methoxy-6-(trifluoromethyl)pyrimidin-2-yl)-4-methyloxazolidin-2-onefrom step 10 (33.0 mg, 0.12 mmol) in THF (4 mL) at −78° C. was addedn-butyllithium (0.07 mL, 0.12 mmol). The reaction mixture was stirred at−78° C. for 5 min, then diphosgene (0.01 mL, 0.12 mmol) was added. Theresulting reaction mixture was stirred at −78° C. for 30 min, thenwarmed to rt. The reaction mixture was concentrated, and the resultingresidue was treated with DCM (4 mL), isoquinolin-4-ylmethanaminedihydrochloride (41.3 mg, 0.178 mmol) and TEA (0.10 mL, 0.71 mmol). Theresulting mixture was stirred at rt for 1 h, then concentrated. Theresulting residue was purified on reverse phase HPLC using acetonitrile(0.05% TFA)/water(0.05% TFA) as mobile phase to give the title compound.LC-MS m/z [M+H]⁺ 462.19 (calc'd 462.13).

Example 97(4S,5R)-5-(3-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)-4-methyl-2-oxo-N-(quinazolin-8-ylmethyl)oxazolidine-3-carboxamide

Step 1:(4S,5R)-5-(3-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one

To a solution of(4S,5R)-5-(3-bromo-5-(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one(200.0 mg, 0.62 mmol, synthesized via steps 1-2 of Example 1) and3,3-difluoropyrrolidine HCl (89.0 mg, 0.62 mmol) in dioxane (2 mL) in amicrowave tube were added Pd₂(dba)₃ (11.3 mg, 0.01 mmol), sodiumtert-butoxide (65.2 mg, 0.68 mmol) and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (Xantphos,28.6 mg, 0.05 mmol). The tube was capped, degassed and filled withnitrogen. Reaction was heated at 80° C. for 12 h. The reaction mixturewas cooled to rt and diluted with ethyl acetate (50 mL), washed withbrine, dried with Na₂SO₄, filtered and concentrated. Purification byflash chromatography (0% to 50% EtOAc in hexane) provided the titlecompound. LC-MS m/z [M+H]⁺ 351.13 (calc'd 351.11).

Steps 2 and 3

(4S,5R)-5-(3-(3,3-difluoropyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)-4-methyl-2-oxo-N-(quinazolin-8-ylmethyl)oxazolidine-3-carboxamidewas synthesized from the product of Step 1 following the procedures ofSteps 3 and 4 of Example 1. LC-MS m/z [M+H]⁺ 536.33 (calc'd 536.17).

TABLE 8 Example 98 was prepared according to the procedure of Example97. Calc'd Observed Example Mass Mass Number Structure Name M + H⁺ M +H⁺ 98

(4S,5R)-5-[3- (dimethylamino)-5- (trifluoromethyl) phenyl]-N-(isoquinolin-4- ylmethyl)-4-methyl- 2-oxo-1,3- oxazolidine-3-carboxamide 473.18 473.03

Example 99(4S,5R)-5-(3-fluoro-5-(trifluoromethyl)phenyl)-4-(2-hydroxyethyl)-N-(isoquinolin-4-ylmethyl)-2-oxooxazolidine-3-carboxamide

Step 1: tert-Butyl(S)-(4-(benzyloxy)-1-(methoxy(methyl)amino)-1-oxobutan-2-yl)carbamate

(S)-4-(benzyloxy)-2-((tert-butoxycarbonyl)amino)butanoic acid (4.48 g,14.48 mmol) in THF (30 mL) was cooled to 0° C., then1-hydroxybenzotriazole hydrate (2.40 g, 15.64 mmol),N,O-dimethylhydroxylamine hydrochloride (1.70 g, 17.38 mmol), DIPEA (6.2mL, 35.3 mmol) and EDC (3.47 g, 18.10 mmol) were added. The reaction wasstirred at rt overnight, then diluted with EtOAc and washed with 1 N HCl(lx), brine (lx), dried (Na₂SO₄), filtered and concentrated to give thetitle compound. LC-MS m/z [M+Na]⁺375.27 (calc'd 375.29)

Step 2: tert-butyl(S)-(4-(benzyloxy)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-oxobutan-2-yl)carbamate

The title compound was prepared according to the procedure of Step 1 ofExample 1. LC-MS m/z [M+H]⁺ 456.20 (calc'd 456.17)

Step 3:(4S,5R)-4-(2-(benzoxy)ethyl)-5-5(3-fluoro-5-(trifluoromethylphenyl)-N-(isoquinolin-4-ylmethyl)-2-oxooxazolidine-3-carboxamide

The title compound was prepared according to the procedure of Steps 3and 4 of Example 1.

Step 4:(4S,5R)-5-(3-fluoro-5-(trifluoromethyl)phenyl)-4-(2-hydroethyl)-N-(isoquinolin-4-ylmethyl)-2-oxooxazolidine-3-carboxamide

(4S,5R)-4-(2-(benzyloxy)ethyl)-5-(3-fluoro-5-(trifluoromethyl)phenyl)-N-(isoquinolin-4-ylmethyl)-2-oxooxazolidine-3-carboxamide(64.4 mg, 0.11 mmol) was dissolved in DCM (5 mL) and the solution wascooled to −78° C. Then pentamethylbenzene (84.0 mg, 0.57 mmol) wasadded, followed by boron trichloride in DCM (0.11 mL, 1 M, 0.11 mmol).The reaction mixture was warmed to 0° C. for 1 h, then cooled to −78° C.Then BCl₃ (0.11 mL, 1 M, 0.11 mmol) was added to the reaction, which waskept at −78° C. for another hour. The reaction mixture was diluted withEtOAc and washed with saturated NaHCO₃ solution (1×), brine (1×), thendried (Na₂SO₄), filtered and concentrated. The resulting residue waspurified by flash chromatography (0% to 100% EtOAc in hexane) to givethe title compound. LC-MS m/z [M+H]⁺ 478.77 (calc'd 478.13).

TABLE 9 Example 100 was prepared according to the procedure of Example65. Calc'd Observed Example Mass Mass Number Structure Name M + H⁺ M +H⁺ 100

(4S,5R)-5-(3,5- bis(trifluoromethyl) phenyl)-3-((E)-3-(isoquinolin-4-yl) acryloyl)-4- methyloxazolidin- 2-one 495.11 495.07

Example 101(R)-7-(3,5-bis(trifluoromethyl)phenyl)-4-(3-(isoquinolin-4-yl)propanoyl)-6-oxa-4-azaspiro[2.4]heptan-5-one

Step 1:(R)-7-(3,5-bis(trifluoromethyl)phenyl)-6-oxa-4-azaspiro[2.4]heptan-5-one

Racemic7-(3,5-bis(trifluoromethyl)phenyl)-6-oxa-4-azaspiro[2.4]heptan-5-one wasprepared according to the procedures in Steps 1-3 of Example 1. LC-MSm/z [M+H]⁺ 326.20 (calc'd 326.05). The racemic material was resolved byAS chiral column using 10% IPA/CO₂ to give the (R)-isomer and the(S)-isomer.

Step 2:(R)-7-(3,5-bis(trifluoromethyl)phenyl)-4-(3-(isoquinolin-4-yl)propanoyl)-6-oxa-4-azaspiro[2.4]heptan-5-one

The title compound was prepared according to the procedure of Step 3 ofExample 65. LC-MS m/z [M+H]⁺ 509.18 (calc'd 509.12).

EXAMPLE OF A PHARMACEUTICAL COMPOSITION

As a specific embodiment of an oral pharmaceutical composition, a 100 mgpotency tablet is composed of 100 mg of any one of the Examples, 268 mgmicrocrystalline cellulose, 20 mg of croscarmellose sodium, and 4 mg ofmagnesium stearate. The active, microcrystalline cellulose, andcroscarmellose are blended first. The mixture is then lubricated bymagnesium stearate and pressed into tablets.

BIOLOGICAL ASSAYS

TarO Biochemical Enzymatic Assay

Assay Background

The pathway for the biosynthesis of wall teichoic acid (WTA) inStaphylococci involves a series of biochemical enzymatic reactions byproteins encoded by the tar genes (teichoic acid ribitol). The firstenzymatic step in the synthesis of WTA is initiated by TarO,N-acetylglucosaminyl-1-P transferase, which catalyzes the transfer ofN-acetyl-glucosamine-phosphate (GlcNAc-P) to an undecaprenyl phosphate(C55-P), also known as bactoprenyl phosphate, to generate C55-PP-GlcNAc(LIPID III). This assays measure the ability of a TarO inhibitor tospecifically inhibit the formation of C55-PP-GlcNAc (LIPID III) productthereby blocking the synthesis of the WTA polymer.

TarO Biochemical Enzymatic Assay Protocol

The TarO biochemical enzymatic assay is a liquid chromatography-massspectroscopy (LC-MS) based end point assay that measures C55-P-P-GlcNAc(LIPID III) production. The TarO biochemical enzymatic assay wasperformed in a 384-well microtiter plate (Labcyte) with a reactionvolume of 20 μl. The reaction mix contained 0.1 μgs/μl of TarO membranepreparation derived from MRSA COL (lysostaphin/lysozyme treated,centrifuged at 40K rpm, and re-suspended in 50 mM Tris pH 7.5, 10 mMMgCl₂), 1500 μM UDP-GlcNAc, x 75 μM C55-P substrates in 83 mM Tris pH8.0, 6.7 mM MgCl2, 6 mM CHAPS, and 8.3% DMSO buffer. The enzymereactions were quenched by extraction in 40 μl of 1-pentanol containing0.04 μM 15C C55-PP-GlcNAc, which was used as an internal standard. A 10μl volume of the quenched reaction mixture (pH≈3) from each well wasinjected onto a reversed-phase column (C4, 5 m, 2.1×50 mm, ThermoScientific Biobacis-4) and eluted using a NH₄Ac/H₂O/MeOH gradient(solvent A: 10 mM NH₄Ac in water, pH 5.6; solvent B: NH₄Ac (1M)-Isopropanol (1:90, v/v, pH 5.6). The HPLC conditions were as follows:15% solvent B for 15 seconds followed by a gradient to 90% solvent B in90 seconds; then solvent B was kept at 95% for 10 seconds followed by agradient to 8% solvent B in 0.1 minute. The column was then equilibratedat 15% B for 1 minute before the next injection. The flow rate was keptconstant at 600 μl/minute. Mass spectrometric detection was carried outin the negative-ion mode using selected reaction monitoring (SRM).Typical mass spectrometric conditions were as follows: heated capillarytemperature, 210° C.; spray voltage, 2500 V; desolvation gas (N₂), 40l/h; auxiliary gas (N₂), 35 l/h. Selected ion current (SIC)chromatograms of C55-PP-GlcNAc and internal standard 15C C55-PP-GlcNAcwere plotted and integrated using LCQuan incorporated in Xcalibursoftware (ThermoFinnigan). The linearity of C55-PP-GlcNAc concentrationversus mass spectrometric signal (AC55-PP-GlcNAc/A15C-C55-PP-GlcNAc) wasdetermined with purified C55-PP-GlcNAc. The IC₅₀ values were calculatedusing the nonlinear regression analysis (sigmoidal dose response fitallowing for a variable slope) of percent inhibition data with minimumand maximum values set to 0 and 100 percent.

The compounds of the present invention, including the compounds inExamples 1-101, have IC₅₀ values less than 100 micromolar (μM) in theTarO Biochemical Enzymatic Assay described above. Preferred compounds ofthe present invention have IC₅₀ values less than 100 nanomolar (nM) inthe TarO Biochemical Enzymatic Assay described above. TarO BiochemicalEnzymatic Assay IC₅₀ values for specific compounds are listed in TableI.

TarO Inhibitor/β-Lactam Synergy Assay

Assay Background

The TarO inhibitor/β-lactam synergy assay was performed to measure there-sensitization of methicillin-resistant Staphylococci bacteria(MB5393: MRSA COL) to β-lactam antibiotics by TarO inhibitors. MRSA COLis a hospital-acquired penicillinase-negative clinically isolated straincommonly used in Staphylococcus aureus studies and is fully resistant tothe antimicrobial bioactivity of β-lactam antibiotics, including but notlimited to imipenem and dicloxacillin. The breakpoint concentrations(measure of susceptibility or resistance to a particular antibiotic) ofβ-lactam antibiotics have been established by the Clinical andLaboratory Standard Institute (CLSI); the clinical breakpoint forimipenem (IPM) is currently 4 μg/ml, and dicloxacillin (DCX) iscurrently 8 μg/ml. MRSA COL is fully refractory to β-lactam antibioticeffect at the current clinical breakpoint concentrations and as suchMRSA COL is fully viable at these concentrations. When administered totreat MRSA as single therapeutic agents, the breakpoint concentrationsof imipenem and dicloxacillin are significantly higher than the currentclinical therapeutic threshold.

TarO Inhibitor/β-Lactam Synergy Assay Protocol

The β-lactam antibiotic concentration was fixed at the clinicalbreakpoint (imipenem 4 μg/ml or dicloxacillin 8 μg/ml) and the TarOinhibitors were titrated by 2 fold starting from the highestconcentration of 200 μM with final DMSO concentration of 2% in theassay. 5×10⁵ colony forming unit of MRSA COL in cation-adjusted MuellerHinton broth (CAMHB) was then mixed and the assay plate was incubatedfor 20 hours at 37° C. without shaking. After 20 hours, the opticaldensity at 600 nm (OD600) was read for all wells to determine relativegrowth of MRSA COL. The MITC₉₅ concentration for imipenem alone wasdetermined to be 32 μg/ml; the MITC₉₅ concentration of dicloxacillinalone was determined to be 128 μg/ml. The MITC₉₅ values determinedfor: 1) the TarO inhibitors alone; 2) the combination of a TarOinhibitor+4 μg/mL of imipenem (IPM); and 3) the combination of a TarOinhibitor+8 μg/mL of dicloxacillin (DCX) are shown in Table I.

The present invention shows that treatment of MRSA bacteria with a TarOinhibitor in combination with a β-lactam antibiotic (imipenem ordicloxacillin) reduces the concentration of β-lactam antibiotic requiredto render MRSA COL susceptible to β-lactam antibiotic treatment belowthe current clinical breakpoint concentration. When MRSA COL was treatedwith imipenem alone in the TarO inhibitor/β-lactam synergy assaydescribed above, the inhibition of MRSA COL viability was not achieveduntil the imipenem concentration was greater than 32 μg/ml (8 foldhigher than breakpoint). Further, when MRSA COL was treated withdicloxacillin alone in the TarO inhibitor/β-lactam synergy assaydescribed above, the inhibition of MRSA COL viability was not achieveduntil the dicloxacillin concentration was greater than 128 μg/ml (16fold higher than breakpoint). However, the TarO inhibitors tested incombination with the β-lactam antibiotics imipenem and dicloxacillinshowed a synergistic bactericidal effect resulting in the inhibition ofMRSA COL at the current breakpoint values of imipenem (4 μg/mL) anddicloxacillin (8 μg/mL). As shown in Table I, the combination of a TarOinhibitor and imipenem showed a synergistic bactericidal effect whenadministered to treat MRSA COL because a concentration of 4 μg/mL ofimipenem was sufficient to inhibit MRSA COL viability when administeredin the combination with a TarO inhibitor, whereas as a concentration of32 μg/mL of imipenem was required to inhibit MRSA COL when administeredalone. Additionally, as shown in Table I, the combination of a TarOinhibitor and dicloxacillin also showed a synergistic bactericidaleffect when administered to treat MRSA COL because a concentration of 8μg/mL of dicloxacillin was required to inhibit MRSA COL viability in thecombination whereas a concentration of 128 μg/mL of dicloxacillinrequired to inhibit MRSA COL when administered alone.

TABLE I Inhibition of TarO and Treatment of MRSA COL with a TarOInhibitor, alone and in combination with Imipenem (IPM, concentration 4μg/mL) or Dicloxacillin (DCX, concentration 8 μg/mL) MITC₉₅ (μM) MITC₉₅(μM) MITC₉₅ (μM) TarO TarO TarO Example inhibitor inhibitor +inhibitor + number TARO alone²; 4 μg/mL IPM³; 8 μg/mL DCX⁴; TarOinhibitor Bacteria: Bacteria: Bacteria: inhibitor IC₅₀ (μM)¹ SA_MB5393SA_MB5393 SA_MB5393 1 0.03 >200 0.03 0.39 2 0.01 >200 0.01 0.21 30.01 >200 0.33 2.60 4 0.01 >200 0.13 0.39 5 0.02 >200 0.09 0.71 60.02 >200 0.01 0.02 7 0.03 >200 0.05 0.33 8 0.03 >200 0.13 1.32 90.04 >200 0.22 1.65 10 0.05 >200 0.06 0.37 11 0.05 >200 0.13 1.42 120.06 >200 0.25 1.56 13 0.10 >200 0.06 0.35 14 0.12 >200 0.49 5.63 150.13 >200 0.98 4.69 16 0.14 >200 0.38 3.52 17 0.15 >200 0.39 4.30 180.16 >200 0.23 1.95 19 0.16 >200 0.15 1.45 20 0.16 >200 0.43 3.65 210.17 >200 0.16 1.73 22 0.19 >200 0.49 6.25 23 0.20 >200 0.61 4.84 240.22 >200 0.20 7.29 25 0.24 >200 0.22 1.38 26 0.24 >200 0.25 0.99 270.25 >200 0.39 3.65 28 0.26 >200 0.70 4.69 29 0.28 >200 0.78 5.21 300.34 >200 0.68 4.69 31 0.44 >200 0.43 8.33 32 0.45 >200 0.59 4.69 330.49 >200 1.37 9.38 34 0.54 >200 1.95 14.06 35 0.61 >200 0.10 0.98 360.69 >200 6.25 25 37 0.85 >200 0.98 2.73 38 0.91 >200 1.56 25 391.42 >200 0.78 25 40 1.69 >200 18.75 50 41 1.78 >200 1.56 16.67 421.87 >200 0.78 12.50 43 2.65 >200 5.21 42 44 2.97 >200 12.50 25 453.61 >200 4.69 25 46 7.76 >200 6.25 50 47 77 >200 62 50 48 0.01 >2000.13 0.39 49 0.01 >200 0.02 0.13 50 0.17 >200 0.22 0.64 51 1.24 >2001.56 8.33 52 0.03 >200 0.03 0.06 53 0.14 >200 0.39 1.37 54 0.08 >2000.20 0.65 55 0.20 >200 0.30 1.18 56 0.20 >200 0.03 0.13 57 0.21 >2000.33 1.56 58 0.45 >200 1.56 6.25 59 0.87 >200 1.95 10.42 60 0.26 >2000.33 1.45 61 0.06 >200 0.20 0.20 62 0.01 >200 0.19 0.72 63 0.15 >2000.37 1.13 64 0.88 >200 0.94 4.38 65 0.01 >200 0.06 0.20 66 0.00 >2000.03 0.20 67 0.01 >200 0.01 ND 68 0.01 >200 0.01 0.20 69 0.04 >200 0.110.39 70 0.08 >200 0.19 0.91 71 0.13 >200 0.89 ND 72 0.14 >200 0.21 1.5673 0.25 >200 0.56 6.25 74 0.25 >200 0.30 6.25 75 0.41 >200 0.13 0.78 760.42 >200 0.39 ND 77 1.07 >200 0.63 5.21 78 1.81 >200 1.17 ND 791.88 >200 1.17 12.50 80 3.00 >200 4.69 ND 81 3.00 >200 0.75 100.00 824.64 >200 9.38 ND 83 0.06 >200 0.06 0.59 84 0.48 >200 1.56 100 850.54 >200 0.55 25.00 86 1.20 >200 1.41 8.33 87 1.20 >200 2.08 50 881.49 >200 1.30 6.25 89 6.98 >200 6.25 75 90 0.68 >200 0.39 12.50 910.04 >200 0.76 4.69 92 0.24 >200 0.51 7.50 93 0.03 >200 0.13 0.50 941.26 >200 3.52 44 95 0.95 >200 5.21 4.17 96 2.17 >200 4.17 25 970.26 >200 0.42 3.32 98 0.03 >200 0.01 0.41 99 4.77 >200 18.75 100 100ND >200 1.60 ND 101 ND >200 0.20 ND ND is not determined. MITC₉₅(minimum inhibitory threshold concentration) is the minimumconcentration required to inhibit MRSA COL growth by 95%. ¹TarO IC₅₀(50% inhibitory concentration) is a measure of biochemical inhibition ofTarO enzymatic activity. ²The minimum concentrations of TarO inhibitorsalone of >200 μM are designated as not having achieved 95% growthinhibition or having no growth inhibitory effect in the in vitro assay.³The minimum concentrations of the TarO inhibitors of the presentinvention required to achieve MITC₉₅ when administered in combinationwith 4 μg/mL of imipenem (IPM). ⁴The minimum concentrations of the TarOinhibitors of the present invention required to achieve MITC₉₅ whenadministered in combination with 8 μg/mL of dicloxacillin (DCX).In Vivo Murine Systemic Infection ModelBackground

The murine systemic infection model determines the therapeutic efficacyof TarO inhibitor/β-lactam combinations in vivo. Staphylococci bacteriacan cause a systemic infection and establish a robust growth in thekidneys of the infected animal. MRSA COL can establish an infection evenin the presence of β-lactam antibiotic due MRSA COL resistance toβ-lactam antibiotics. In this model, therapeutic efficacy is achievedwhen bacteria recovered from the TarO inhibitor/β-lactam antibioticcombination is greater than 100 fold lower than the vehicle alonecontrol group.

Protocol

Female Balb/C mice were rendered neutropenic (immune suppressed) with asingle 250 mg/kg intraperitoneal (ip) dose of cyclophosphamide on Day 4.MRSA COL (MB 5393) was grown for 16 hours in trypticase soy broth (TSB)at 37° C. and 0.5 mL of diluted culture (˜1×10⁴ cfu) was administeredintraperitoneal (IP). The TarO inhibitor and β-lactam antibiotic wereadministered alone or in combination by subcutaneous route at 2, 5 and 8hr. post challenge (sc, tid). Twenty four hours post challenge mice wereeuthanized and the kidneys harvested, weighed, homogenized and plated tomeasure the total number of bacteria recovered as colony forming unit(CFU) remaining in compound treated groups as compared to vehicle(saline) or β-lactam antibiotic alone groups (statistical analyses wasdetermined by one way ANOVA).

As shown in Table II, the TarO inhibitor of Example 18 alone resulted inthe number of bacteria recovered in colony forming units/gram of kidneyof 6.6×10⁷ (−0.9 fold lower), and the combination of TarO inhibitor ofExample 18 and dicloxacillin reduced the number of bacteria recovered incolony forming units/gram of kidney to 4. 1×10⁴ (1463 fold lower).

TABLE II Results of In Vivo Murine Systemic Infection Model Bacteriarecovered Fold reduction vs. Treatment Groups [cfu/g kidney] vehiclealone Vehicle alone 6.0 × 10⁷ Not Applicable saline control Imipenemalone 1.3 × 10⁷ 4.6 (5 mg/kg) Example 18 alone 6.6 × 10⁷ −0.9 (50 mg/kg)Example 18 4.1 × 10⁴ 1463.4 (50 mg/kg) + Imipenem (5 mg/kg) Data is anaverage of 5 mice for each treatment group

The scope of the claims should not be limited by the preferredembodiments set forth in the examples, but should be given the broadestinterpretation consistent with the description as a whole.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the scope of the invention. For example,effective dosages other than the particular dosages as set forth hereinabove may be applicable as a consequence of variations in responsivenessof the mammal being treated for any of the indications with thecompounds of the invention indicated above. The specific pharmacologicalresponses observed may vary according to and depending upon theparticular active compounds selected or whether there are presentpharmaceutical carriers, as well as the type of formulation and mode ofadministration employed, and such expected variations or differences inthe results are contemplated in accordance with the objects andpractices of the present invention.

What is claimed is:
 1. A composition having a structure selected fromthe group consisting of:

or pharmaceutically acceptable salts thereof.
 2. A pharmaceuticalcomposition comprising synergistic combination of a beta-lactamantibiotic, wherein the beta-lactam antibiotic is cephalexin, imipenem,or dicloxacillin; a pharmaceutically acceptable carrier; and a TarOinhibitor compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein A is selectedfrom the group consisting of: (1) aryl, (2) heteroaryl, (3) —O-aryl, and(4) —O-heteroaryl, wherein aryl and heteroaryl are unsubstituted orsubstituted with 1-5 substituents selected from R^(a); B is selectedfrom the group consisting of: (1) aryl, and (2) heteroaryl, wherein aryland heteroaryl are substituted, and wherein aryl and heteroaryl aresubstituted with 0-4 substituents selected from R^(b1) and 0-1substituents selected from R^(b2) _(;) X is CR⁸R⁹; Y is selected fromthe group consisting of: (1) NR³, and (2) —CR¹⁰R¹¹; R¹ is selected fromthe group consisting of: (1) —C₁₋₆alkyl, and (2) —(CH₂)_(p)—OH, whereinCH₂ and alkyl are unsubstituted or substituted with 1-2 substituentsselected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl; R² is selected fromthe group consisting of: (1) hydrogen, and (2) —C₁₋₆alkyl, wherein alkylis unsubstituted or substituted with 1-2 substituents selected from:halogen, —C₁₋₆ alkyl, and —OC₁₋₆alkyl, or R¹ and R² together with thecarbon atom they are attached to form a C₃₋₆cycloalkyl ring, wherein thecycloalkyl ring is unsubstituted or substituted with 1-2 substituentsselected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl; R³ is selected fromthe group consisting of: (1) hydrogen, and (2) —C₁₋₆alkyl, wherein alkylis unsubstituted or substituted with one to five substituents selectedfrom —C₁₋₆alkyl; each R⁴ is independently selected from the groupconsisting of: (1) hydrogen, (2) halogen, (3) —C₁₋₆alkyl, and (4)—(CH₂)_(p)—OH, wherein CH₂ and alkyl are unsubstituted or substitutedwith 1-2 substituents selected from: halogen, —C₁₋₆alkyl, and—OC₁₋₆alkyl; each R⁵ is independently selected from the group consistingof: (1) hydrogen, (2) halogen, (3) —C₁₋₆alkyl, and (4) —(CH₂)_(p)—OH,wherein CH₂ and alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl; R⁶ isselected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, and(3) —(CH₂)_(p)—OH, wherein CH₂ and alkyl are unsubstituted orsubstituted with 1-2 substituents selected from: halogen, —C₁₋₆alkyl,and —OC₁₋₆alkyl; R⁸ is selected from the group consisting of: (1)hydrogen, and (2) —C₁₋₆alkyl, wherein alkyl is unsubstituted orsubstituted with 1-2 substituents selected from: halogen, C₁₋₆ alkyl,and —OC₁₋₆alkyl; R⁹ is selected from the group consisting of: (1)hydrogen, and (2) —C₁₋₆alkyl, wherein alkyl is unsubstituted orsubstituted with 1-2 substituents selected from: halogen, —C₁₋₆alkyl,and —OC₁₋₆alkyl; R¹⁰ is selected from the group consisting of: (1)hydrogen, (2) —C₁₋₆alkyl, and (3) —(CH₂)_(p)—OH, wherein CH₂ and alkylare unsubstituted or substituted with 1-2 substituents selected from:halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl; R₁₁ is selected from the groupconsisting of: (1) hydrogen, (2) —C₁₋₆alkyl, and (3) —(CH₂)_(p)—OH,wherein CH₂ and alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl; eachR^(a) is independently selected from the group consisting of: (1)halogen, (2) —C₁₋₆alkyl, (3) —OC₁₋₆alkyl, (4) —OC₁₋₆alkenyl, (5) —OH,(6) oxo, (7) —CN, (8) —NO₂, (9) —NR^(c)l R^(d), (10) —CH₂NR^(c)R^(d),(11) —SO₂C₁₋₆alkyl, (12) —C₃₋₆cycloalkyl, (13) —C₂₋₆cycloheteroalkyl,(14) aryl, and (15) heteroaryl, wherein —CH_(2,) alkyl, alkenyl,cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted orsubstituted with 1-4 substituents selected from: halogen, —C₁₋₆alkyl,—OC₁₋₆alkyl, and —CO₂C₁₋₆alkyl; each R^(b1) is independently selectedfrom the group consisting of: (1) halogen, (2) —C₁₋₆alkyl, (3)—C₂₋₆alkenyl, (4) —CN, (5) —NO₂, (6) —NR^(c)R^(d), (7) —SO₂C₁₋₆alkyl,(8) —C₃₋₆cycloalkyl, (9) —C₂₋₆cycloheteroalkyl, (10) aryl, and (11)heteroaryl, wherein alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryland heteroaryl are unsubstituted or substituted with 1-4 substituentsselected from: halogen, —C₁₋₆alkyl, —OC₁₋₆alkyl, and —CO₂C₁₋₆alkyl; eachR^(b2) is independently selected from the group consisting of: (1)—OC₁₋₆alkyl, (2) —OC₂₋₆alkenyl, (3) —OH, (4) oxo, wherein alkyl, alkenylare unsubstituted or substituted with 1-4 substituents selected from:halogen, —C₁₋₆alkyl, —OC₁₋₆alkyl, and —CO₂C₁₋₆alkyl; each R^(c) isindependently selected from the group consisting of: (1) hydrogen, (2)C₁₋₆alkyl, (3) C₂₋₆alkenyl, (4) C₁₋₆alkyl—OH, (5) C₃₋₆cycloalkyl, (6)C(O)C₁₋₆alkyl, and (7) SO₂C₁₋₆alkyl, wherein alkyl, alkenyl andcycloalkyl are unsubstituted or substituted with one to threesubstituents selected from halogen, —C₁₋₆alkyl, —OC₁₋₆alkyl, and—CO₂C₁₋₆alkyl; each R^(d) is independently selected from the groupconsisting of: (1) hydrogen, (2) C₁₋₆alkyl, (3) C₂₋₆alkenyl, (4)C₁₋₆alkyl—OH, (5) C₃₋₆cycloalkyl, (6) C(O)C₁₋₆alkyl, and (7)SO₂C₁₋₆alkyl, wherein alkyl, alkenyl and cycloalkyl are unsubstituted orsubstituted with one to three substituents selected from halogen,—C₁₋₆alkyl, —OC₁₋₆alkyl, and —CO₂C₁₋₆alkyl, or R^(c) and R^(d) togetherwith the nitrogen atom they are attached to form a C₄₋₈cycloheteroalkylring, wherein the C₄₋₈cycloheteroalkyl ring is unsubstituted orsubstituted with 1-4 substituents selected from halogen, —C₁₋₆alkyl,—OC₁₋₆alkyl, and —CO₂C₁₋₆alkyl; m is 0 or 1; n is 0, 1, 2 or 3; and p is0, 1, 2, 3, 4, 5 or
 6. 3. The pharmaceutical composition according toclaim 2, wherein A is selected from the group consisting of: (1) aryl,(2) heteroaryl, and (3) —O-aryl, wherein aryl and heteroaryl areunsubstituted or substituted with 1-5 substituents selected from R^(a);or a pharmaceutically acceptable salt thereof.
 4. The pharmaceuticalcomposition according to claim 2, wherein A is selected from the groupconsisting of: (1) aryl, and (2) heteroaryl, wherein aryl and heteroarylare unsubstituted or substituted with 1-5 substituents selected fromR^(a); or a pharmaceutically acceptable salt thereof.
 5. Thepharmaceutical composition according to claim 2, wherein B is aryl,wherein aryl is unsubstituted or substituted with 1-4 substituentsselected from R^(b); or a pharmaceutically acceptable salt thereof. 6.The pharmaceutical composition according to claim 2, wherein B isheteroaryl, wherein heteroaryl is unsubstituted or substituted with 1-4substituents selected from R^(b); or a pharmaceutically acceptable saltthereof.
 7. The pharmaceutical composition according to claim 2, whereinY is —CR¹⁰R¹¹ or a pharmaceutically acceptable salt thereof.
 8. Thepharmaceutical composition according to claim 2, wherein Y is NR³; or apharmaceutically acceptable salt thereof.
 9. The pharmaceuticalcomposition according to claim 2, wherein R¹ is selected from the groupconsisting of: (1) hydrogen, (2) —C₁₋₆alkyl, and (3) —(CH₂)_(p)—OH,wherein CH₂ and alkyl are unsubstituted or substituted with 1-2substituents selected from: halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl; or apharmaceutically acceptable salt thereof.
 10. The pharmaceuticalcomposition according to claim 2, wherein R¹ is selected from the groupconsisting of: (1) hydrogen, and (2) —C₁₋₆alkyl, wherein alkyl isunsubstituted or substituted with 1-2 substituents selected from:halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl; or a pharmaceutically acceptablesalt thereof.
 11. The pharmaceutical composition according to claim 2,wherein R² is selected from the group consisting of: (1) hydrogen, (2)—C₁₋₆, and (3) —(CH₂)_(p)—OH, wherein CH₂ and alkyl are unsubstituted orsubstituted with 1-2 substituents selected from: halogen, —C₁₋₆alkyl,and —OC₁₋₆alkyl, or R¹ and R² together with the carbon atom they areattached to form a C₃₋₆cycloalkyl ring, wherein the cycloalkyl ring isunsubstituted or substituted with 1-2 substituents selected from:halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl; or a pharmaceutically acceptablesalt thereof.
 12. The pharmaceutical composition according to claim 2,wherein R² is selected from the group consisting of: (1) hydrogen, (2)—C₁₋₆alkyl, and (3) —(CH₂)_(p)—OH, wherein CH₂ and alkyl areunsubstituted or substituted with 1-2 substituents selected from:halogen, —C₁₋₆alkyl, and —OC₁₋₆alkyl; or a pharmaceutically acceptablesalt thereof.
 13. The pharmaceutical composition according to claim 2,wherein R³ is selected from the group consisting of: (1) hydrogen, and(2) OH; or a pharmaceutically acceptable salt thereof.
 14. Thepharmaceutical composition according to claim 2, wherein R³ is hydrogen;or a pharmaceutically acceptable salt thereof.